Heart

Failure
Drugs Used in HF:
→ Diuretics (reduce blood volume):
o Thiazide diuretics: preferred over loop diuretics in pts with mild fluid retention and inc BP
o Loop diuretics: necessary to restore and maintain euvolemia in HF; maintain effectiveness even with impaired renal function
o Aldosterone antagonists: attenuate cardiac fibrosis and remolding; combined with ACE-I; decrease pro-inflammatory state and oxidative stress caused by aldosterone

→ Vasodilators: reduce peripheral resistance
o ACE-I: dec afterload, dec peripheral resistance; dec Na+ and H2O retention!dec preload
Positive inotropyà increase in CO
o ARBs
Positive chronotropyà increase in HR
o Renin inhibitors Positive Dromotropyà increase in conduction velocity
→ Cardioinhibitory drugs (reduce HR and contractility)!B-blockers, Ca2+ channel blockers Positive lusitropyà increase in rate of relaxation
→ Inotropic agents (Stimulate contractility)!digoxin
→ Inotropic agents used in ACUTE HF! Inamrinone, Milrinone, dopamine, dobutamine, glucagon
Classification of HF according to NYHA
Classification of HF according to AHA → Class I: no symptom limitation with ordinary physical activity
→ Stage A: High risk of developing heart failure [selected pts receive ACE-I’s/ARB’s] → Class II: ordinary physical activity somewhat limited by dyspnea (long walks, climbing 2
→ Stage B: Asymptomatic heart failure [selected pts receive ACE-I’s/ARB’s or β-blocker] stairs)
→ Stage C: Symptomatic heart failure [routine drugs include diuretics, ACE-I & β-blocker] → Class III: exercise limited by dyspnea w/ moderate workload (short walks, climbing 1
→ Stage D: Refractory end stage heart failure [end of life care or extraordinary measures] stairs)
→ Class IV: dyspnea at rest w/ very little exertion
→ Heart failure occurs when the CO is inadequate to provide the O2 needed by the body
→ SXS: tachycardia, ↓ exercise tolerance, dyspnea, peripheral and pulmonary edema, cardiomegaly
→ Most common cause in the US is CAD and HTN
→ Systolic failure (HFrEF): dec contractility (associated with a dilated ventricle)!dec SV!inc EDV!dec EF!inc in preload d/t compensatory action of inc blood volume
→ Diastolic failure (HFpEF): stiffening and loss of adequate relaxation → abnormal ventricular filling and reduced CO even though the EF may be normal [does not respond to +ve inotropes]
→ CHF: abnormal increase in blood volume and interstitial fluid leading to dyspnea and peripheral edema
→ Physiologic compensation → chronic activation of the SNS and RAAS associated with tissue remodeling → additional neurohormonal activation → viscous cycle → death
There are four factors that affect cardiac performance:
1. Preload (force stretching ventricles): Frank Starling mechanism→ stretching of the myocardial cells
increases contractility, but only up to a certain point after which contractility suffers and CHF begins;
could result in pulm. edema if too high d/t volume overload
2. Afterload: Force against which the ventricles must act; basically dependent on vascular resistance and
aortic blood pressure
3. Contractility: Directly related to intracellular Ca2+ concentration
4. Heart Rate: If HR becomes too fast, there is not enough time to adequately fill the ventricles and CO
decreases; HR increases d/t SNS activation of β1- receptors
Goal of treatment is to minimize the compensatory mechanisms→ reduce symptoms, slow progression and
manage acute episodes
→ Drugs used to treat systolic failure include: diuretics, spironolactone, ACE-I’s, ARB’s, direct vasodilators, β-blockers and inotropic agents
→ Drugs used to treat diastolic failure include: diuretics (txt pulm edema), Ca2+ channel blockers (not used in systolic dysfxn b/c the dec inotropy and SV; improve ventricular relaxation and dec
HR) and β-blockers (improve ventricular relaxation and dec HR); do NOT use +ve inotropes which can lead to increased outflow obstruction















 Drugs Used in Heart Failure
Drug Name Class Description MOA Uses PK Adverse Effects
Chlorthalidone Relieve pulmonary congestion & peripheral edema Loop: more effective than thiazides
Thiazide ^restore / maintain euvolemia in HTN
Hydrochlorothiazide ↓ symptoms of volume overload [orthopnea]
Diuretics effective when impaired renal function
Metolazone Thiazides: pts with hypertensive heart disease [with
↓ plasma volume → ↓ venous return i.e. preload → congestive symptoms]! ineffective by itself due to its
Furosemide Loop Diuretics decreased workload and O2 demand weak diuretic effect
↓ Afterload
Hyperkalemia
GI: gastritis, PUD
Advanced heart disease or pts with LV dysfunction CNS: lethargy, confusion
Prevents Na+ retention, myocardial hypertrophy & K+
Eplerenone Aldosterone after an MI (these pts have elevated aldosterone due Endocrine: gynecomastia, ↓libido,
loss
Spironolactone Antagonist to angiotensin stimulation and reduced hepatic menstrual irregularities
[When combined with ACE-I’s→ ↓M&M of severe HF]
clearance)
Contraindicated in pts on K+
supplements
↓PVR → ↓BP/afterload → Pts with symptomatic HF
DOC in heart failure Oral Persistent dry cough Hypotension
↑CO
Dilates arterioles and Renal insufficiency
Captopril ACE-I Asymptomatic pts with
Reduce veins Food! Hyperkalemia
• preload Enalapril ↓Na+ and H2O retention → ↓LVEF or history of MI
• afterload ↓absorption Angioedema
Lisinopril Vasodilator ↓preload
All pro-drugs except Teratogenic!contraindicated in
High risk pts: diabetes, HTN,
captopril t½ = 2-12 hrs pregnancy
↓long term remodeling atherosclerosis, obesity
Valsartan is used for HTN Hypotension
ARB Candesartan is used for CHF Renal insufficiency
Candesartan No effect on
Block AT-I receptor Oral & 1/day dosing Hyperkalemia
Valsartan bradykinin
Vasodilator Used in pts intolerant to ACE- Teratogenic!contraindicated in
I’s [no cough/angioedema] pregnancy
Combination: Hypotension,
Pt’s that are intolerant to ACEI’s/ARBs or β-blockers or
↑venodilation → ↓preload dizziness, reflex tachycardia,
black patients with advanced HF [adjuvant TXT]
Hydralazine Direct ↑arterial dilation → ↓PVR/↑SV & afterload Na+/H20 retention, GI issues

Isosorbide Dinitrate Vasodilator Hydralazine dilates the arterioles Hydralazine: tachycardia,
Sustained improvement of LVEF when both oral
Nitrates dilates the veins and venules peripheral neuritis and a lupus like
vasodilators are combined oral; dose 3x/day
syndrome
Initial treatment can cause fluid
retention :risks acute decompensation
Start at low dose→ Abrupt withdrawal!unstable
β-blocker
Can reverse cardiac ↓HR and RAAS [-ve inotrope] gradually titrate to angina, MI, death
Carvedilol
ß1 blockers Heart disease [stage B and C]
remodeling and Prevents deleterious effects of effective dose Hypoglycemia
Metoprolol Cardioinhibitory in addition to an ACE-I
reduce mortality NE on cardiac muscle fibers [avoid sudden CNS effects
drugs
• heart failure exacerbation of SXS
• diastolic failure
Use cautiously in pts with asthma
or severe bradycardia/ AV block









 Drugs Used in Heart Failure Continued
Drug Name Class Description MOA PK Adverse Effects
Extensive inhibition of ATPase can lead to dysrhythmias

+ve inotropic Complicated, t½= 36-40h in pts w/
competes with K Toxicity [very common]:
-ve chronotropic + normal renal fxn
Inhibits Na/K ATPase → ↓Na Cardiac: Atrial arrhythmia, AV block

gradient→ indirect inhibition of Anorexia, nausea, vomiting, Headache, fatigue, confusion,
From foxglove plant Widely distributed including the
Na+/Ca2+ exchange→ blurred/yellow vision, altered color perception, halos on
CSF
↑cytoplasmic Ca2+→ dark objects d/t narrow therapeutic window
Widely used in the treatment
↑contractility
of HF & supraventricular Accumulates in muscle→ high Vd;
tachyarrythmia (AFib) Treatment of toxicity: Withdraw or reduce dose; Monitor
requires a loading dose
Inotropic ↓SNS, RAAS & PVR → ↓HR ECG, plasma concentration and K+ levels
Very small difference
Agent: V-tach: treat with lidocaine and Mg2+ or ↑[K+]
Digoxin between therapeutic and Sensitivity varies between
Enhanced vagal tone → ↓O2 Severe toxicity: treat with digitalis antibodies
[digitalis] toxic dose [narrow patients and may change during Hypokalemia increases
Cardiac demand digoxin binding
therapeutic window] therapy
glycoside Hypothyroidism!↑conc. of digoxin Hyperkalemia decreases

↓conduction through AV node; Hyperthyroidism! ↓conc. of digoxin digoxin binding
↓SXS of HF & hospitalization Hypokalemia→ digoxin toxicity
↑effective refractory period Diuretics indirectly act with digoxin to ↓K+ levels Hypercalcemia increases
↑Exercise tolerance [competes with K+ for binding risk of arrhythmia
Quinidine, Verapamil, Amiodarone & NSAIDS displace
Does NOT ↑survival sites on ATPase]
baroreceptor desensitization! digoxin from tissue protein binding sites and compete for Hypomagnesemia
acute sensitizes heart to
sustained elevation of plasma renal excretion!↑conc. of digoxin :depress clearance digoxin-induced
Indicated in pts with heart Hypercalcemia ,↓Mg2+ or arrhythmia
NE
failure with A-fib along with hypokalemia facilitate digoxin
Digoxin binds phosphorylated Contraindicated in: Diastolic or right side HF (leads to
ACE-I and β-blocker NaKATPase. Extracellular K promotes action
dephosphorylation, decreasing outflow obstruction), uncontrolled HTN, bradyarrhythmias,
affinity for digoxin
non-responders/ intolerant pts, and hypokalemic pts
PDE-III inhibitor
↑cAMP→ +ve inotropic effects and ↑CO [similar to β1] Arrhythmia Long-term therapy increases mortality
Milrinone
Systemic and pulmonary vasodilation→ ↓preload and afterload Hypotension
Inamrinone IV for acute/short term ↑CO
Slight ↑AV conduction Thrombocytopenia (more common with inamrinone)
in pts w/ intractable HF
Low dose: D1 → dilate renal and mesenteric blood vessels! may
Used in the treatment of
induce natiuresis and ↑urine output Arrhythmia
shock that persists after

volume replacement
Dopamine Intermediate dose: dopaminergic and β1 receptors→ ↑ force and High doses!↑myocardial O2 demand!worsen ischemia in

D1>ß1>a1 Inotropic rate of contraction and renal vasodilation some pts with CAD
Stimulates both α1, β1/β2 and
Agents
dopaminergic (D1) receptors
High dose: α1 receptors→ vasoconstriction [not helpful]
Β-agonist +ve inotropic effects and vasodilation
Racemic mixture ↑cAMP [Gs]→ … phosphorylation of Ca2+ channels with ↑Ca2+ entry
Dobutamine into myocardium→ ↑contraction less arrhythmogenic than dopamine
Used to ↑CO in acute mgmt. Little or no effect on HR
• ß1 agonist
• mild ß2 agonist

of HF(cardiogenic shock, MI) ↑CO w/o inc O2 demands!major advantage

Mgmt. of severe β-blocker Gs→ ↑cAMP→ ↑contractility [without using β-receptors]
Glucagon
indirect functional agonist
overdose +ve inotropic & chronotropic effects
HF Treatment Conclusions
→ All pts w/ HF and systolic dysfxn should take an ACE-I, a β-blocker, AND a diuretic (if volume overloaded)
→ ARBs!pts who can’t tolerate an ACE-I
→ Aldosterone antagonist! addition to triple therapy can be beneficial for pts with moderate-severe HF or pts w/ LV dysfxn after an MI
→ Hydralazine/isosorbide dinitrate! addition to triple therapy can be beneficial
→ Digoxin! addition to triple therapy can decrease symptoms but NOT increase survival