Pharmacology of Heart Failure 1 & 2 Flashcards
What is the 5 year survival for heart failure?
What causes mortality?
50%
- Sudden death is the most common COD (5x that of general population)
What is this?
Heart failure (nL heart is less than 1/2 the thoracic cage)
What are the physiological problems in congestive heart failure?
Marks of systolic/diastolic failure?
- Decreased contractility (e.g. muscle replaced by fibrous tissue)
a. Systolic heart failure (decreased contractility)
b. Diastolic heart failure (decreased compliance)
- Increased afterload (e.g. atherosclerosis, HTN, less elastic BVs)
- Increased preload (e.g. defective heart valves)
What are characteristics of L vs. R heart failure? Which is more common?
Left heart failure- more common
- Pulmonary congestion
- Blood accumulates in lungs/pulmonary edema
- Eventually systemic edema
Right heart failure
- Ischemia due to blocked coronary arteries
- Systemic congestion
- Blood accumulates in periphery/peripheral edema
What are the broad compensatory changes in response to primary insult in CHF?
- Neurohormonal activation
- Activation of RAAAS system
- Inflammatory cascade activation
- Structural changes to myocardium
What does neurohormonal compensation involve?
- Increased sympathetic neuronal activation (increased NE, increased SVR)
- Decreased PS tone (increased HR)
- Increased vasopressin (ADH)
- Increased aldosterone
- Increased endothelin-1 (constricts sm)
- Increased BNP (B-type natriuretic peptide)
Plasma __ levels predict mortality in patients with CHF. Higher levels = poor prognosis.
Circulating ___ levels correlate with severity of CHF
Mortality
- Plasma NE
- Plasma pro BNP and plasma endothelin (big ET-1)
Severity
- Circulating TNF-a
What is involved in the inflammatory cascade activation in compensation for heart failure?
- Increased reactive oxygen species formation
- Increased cytokine production (e.g. TNFa)
- Circulating inflammatory cell infiltration
- Local inflammatory cell activation
What is involved in the structural changes to myocardium in compensation for heart failure?
- Myocardial architectural disruption
- Abnormal ECM formation
- Myocardial cell realignment (remodeling)
All of the following increase in patients with heart failure, except:
A. Sympathetic input
B. Tumor necrosis factor
C. Angiotensin II
D. Parasympathetic input
E. Aldosterone
F. ADH (Vasopressin)
All of the following increase in patients with heart failure, except:
A. Sympathetic input
B. Tumor necrosis factor
C. Angiotensin II
D. Parasympathetic input
E. Aldosterone
F. ADH (Vasopressin)
Progression from HTN to heart failure (cool pic)
(:
What are the goals for therapy with drugs for heart failure?
- Rapid relief of symptoms
- Reduce mortality, hospitalizations, improve quality of life
- Change the natural history of the disease
- Safe and well tolerated
What drug classes are used in the treatment of heart failure?
- ACEI/ARBs (blockers of ang-aldost syst)
- Inotropic agents (cardiac glycosides)
- Beta adrenergic agonists (Dobutamine, Dopamine, NE)
- PDE3 (PDE inhibs)
- Diuretics (decrease BV/preload)
- Beta blockers (decrease work load on heart)
- CCBs (decrease work load on heart/decrease afterload)
- Vasodilators (decrease afterload)
What drugs are used in acute heart failure?
Chronic heart failure?
What are some cardiac glycosides?
What do they do?
Digitoxin and Digoxin
- Inotropic agents; increase contractility of the heart
- Differ by a single OH group and have differences in kinetics and metabolism (most pts in US are on Digoxin; Digitoxin has a longer half life with less control)
What is the mechanism of action of digitalis?
- Blocks K portion of Na-K-ATPase
- Increases intracellular Na
- Decreases action of Ca-Na exchanger
- Increases intracellular Ca
- Positive inotropic effect
What are the physiological benefits of Digoxin?
- Increased contractility
- > Increased stroke volume
- > Increased cardiac output
- Decreased ventricular EDP
How does increased contractility change the P-V loop response?
- Decreased EDV (?)
- Increased SV
- Increased LV pressure
T/F: Digoxin helps people with CHF feel better?
False- just improved quality of life for the remainder of it
Which of the following class of drugs are NOT recommended to treat ACUTE heart failure?
A. Diuretics
B. Digoxin
C. Beta 1 agonsits
D. Beta blockers
E. ACEI/ARBs
Which of the following class of drugs are NOT recommended to treat ACUTE heart failure?
A. Diuretics
B. Digoxin
C. Beta 1 agonsits
D. Beta blockers
E. ACEI/ARBs
- Not well tolerated at the beginning, but huge advantages chronically (including increased life span)
Explanation for the physiological effects of cardiac glycosides (lengthy)…
Normal heart
- Within limits, when cardiac muscle is stretches, its force of contraction increases and CO increases
- However, if the ventricle is overly stretched, the effect of ventricular contraction is diminished
Decompensated heart failure
- Initial reduction of contractility
- Symptoms of low CO develop (dyspnea, edema) Compensated heart failure
- Ventricular end diastolic pressure increases in an effort to maintain an adequate cardiac output
- The increased ventricular end-diastolic pressure causes symptoms of of congestion (dyspnea)
Digitalis treatment
- Administration of digitalis shifts the ventricular function curve toward normal
- Increased contractility leads to increased CO
- Decreased sympathetic reflexes and vascular tone cause a decrease in the ventricular end diastolic pressure
What are the beneficial kinetic characteristics of digoxin?
- Bioavailability
- Onset of action
- Half life
- Excretion method/amt
- Volume of distribution
- Bioavailability: oral ~ 75%
- Rapid onset of action, ~20%
- Half-life of 36 hours (Digitoxin is about 5 days)
- Renal excretion (~90%)
- Large volume of distribution; binds to Na/K ATPase in skeletal muscle
What kind of heart failure are cardiac glycosides good for?
What other cardiac conditions?
- SYSTOLIC heart failure
- Supraventricular arrhythmias (NOT ventricular)
What are some adverse effects of cardiac glycosides?
- Arrhythmias
- PVCs (premature ventricular contractions)
- Muscle weakness (drug inhibits muscle Na/K ATPase enzyme)
- Fatigue
What condition increases digitalis toxicity?
Hypokalemia
- Careful if pt is on diuretics which alter K balance (or steroids)!
- Digitalis/digoxin have narrow therapeutic window (~2); toxicity is very common
How can you treat digitalis toxicity?
- Stop digoxin/digitalis
- Control arrhythmias (propranolol, lidocaine, phenytoin, atropine; NOT quinidine)
- Give potassium
- Antiglycoside antibodies (since digoxin is not readily dialyzable)
Digoxin increase cardiac output by:
A. Activating Na/K ATPase pump
B. Inhibiting Na/K ATPase pump
C. Inhibiting Na/Ca exchanger
D. Inhibiting Calcium pump
E. By inhibiting cAMP phosphodiesterase 3
Digoxin increase cardiac output by:
A. Activating Na/K ATPase pump
B. Inhibiting Na/K ATPase pump
C. Inhibiting Na/Ca exchanger
D. Inhibiting Calcium pump
E. By inhibiting cAMP phosphodiesterase 3
What are some phosphodiesterase type III inhibitors?
–rinone
Amrinone (IV) and Milrinone (IV and PO)
What is the mechanism of action of phosphodiesterase type III inhibitors?
- Inhibit PDE III and prevents breakdown of cAMP
In the heart:
- Increase HR, contractility, and CO
In the BVs:
- Relaxes vascular smooth muscle to lower BP
Adverse effects of PDE III inhibitors?
Toxicities
- Hepatic and gastrointestinal
- Thrombocytopenia (in about 10%)
- Arrhythmogenic
Increase mortality; used only short-term/acutely!
Why use beta agonists in CHF (physiological benefits)?
- Acutely improve LV function and increase CO
- Acutely improve tissue perfusion (kidney, heart, brain)
- Acutely decrease pulmonary congestion
What are some beta agonists used in CHF?
- Dobutamine
- Dopamine
What is the mechanism of Dobutamine? Effects?
- Stimulates mostly B1 receps (also some B2 and a1 adrenoreceps)
- Increases contractility and CO
- Decreases afterload (TPR): decreased sympathetic tone as CO improves and direct arterial vasodilation via B2 receps
- Reduces preload (LVEDP): increases LV emptying and increases Na/H2O excretion by increasing renal perfusion
What is the mechanism of dopaminergic agonists? Effects?
Specificity- “Dubai” (DBA1): Dopamine > B1 > a
- Cardiovascular effect is dose-dependent
Low dose (D1 receps)
- Vasodilation in renal, mesenteric, coronary, and cerebral vascular beds
- Promotes sodium and water excretion in kidney
Medium dose (D1 and B1 receps)
Large dose (a recep)
- Vasoconstriction
OVERALL
- Used to preserve renal blood flow, protect vital organs, used to treat cardiogenic shock
- Increased force of contraction >> HR
How do Beta1 agonists and PDE inhibitors work (broad mechanism)?
Increase cAMP levels
What is hydralazine?
- Delivery
- Mechanism
- Physiologic effects
- Adverse reactions
Arterial vasodilator used in CHF
- Orally active
- Mechanism unknown
- Major reduction in afterload
- Minimal venodilation (little orthostatic drop in BP)
- Reflex sympathetic activation
- Fluid retention
Adverse reactions:
- Headache
- Nasal congestion
- Tachycardia
- MI
- Lupus syndrome (+ANA)
What is nitroglycerin?
- Mechanism
- Delivery
- Physiologic effects
- Adverse reactions
Selective venodilator used in CHF
- NO donor
- Decreases preload: decreases venous return, decreases LV filling
- Given IV
- Less reflex tachycardia than hydralazine
- Tolerance develops
- Less fluid retention than hydralazine
Adverse reactions:
- Headache
- Dizziness
- Postural hypotension
- Rash
- Interaction with sildenafil
What is sodium nitroprusside?
- Delivery
- Mechanism
- Adverse reactions
Direct-acting vasodilator used in CHF
- IV only
- Balanced arterial and venodilator
- Reflex tachycardia, fluid retention
Adverse reactions:
- Headache
- Hypotension
- N/V
- Thiocyanate toxicity with renal insufficiency
What are the vasodilators used in CHF?
- Hydralazine
- Nitroglycerin
- Sodium nitroprusside
What diuretics are used in heart failure?
Loop diuretics
- Furosemide (Lasix)
- Bumetanide (Bumex)
- Torsemide (Demadex)
Thiazide-type diuretics (hydrochlorothiazide, chlorthalidone) are not very effective in CHF
- Thiazides are most effective in treating HTN
What are the actual outcomes of Digitalis in chronic heart failure?
- Outcomes?
- Severity dependent?
- Gender differences?
- Race differences?
- Digoxin DOES NOT affect all-cause mortality (primary end point) in systolic heart failure pts with normal sinus rhythm
- Digoxin DOES NOT decrease mortality but MAY reduce hospitalizations in CHF pts
- MAY reduce occurrence of atrial fibrillation in CHF pts
- MAY increase death rates in women compared to men
- Pts with more severe heart failure APPEAR to get more benefit than those with less severe forms of CHF
What are the physiologic benefits and outcomes of using Hydralazine + isosorbide dinitrate?
Epidemiologic nuances?
- Reduces preload/afterload
- Increases LVEF
- Reduces symptoms
- Reduces mortality by 28%
- Most effective in class III-IV CHF
- This regimen is effective in reducing mortality and morbidity in African Americans
What are the physiologic benefits of CCBs?
What are there sites of action?
- SA node: decrease HR
- AV node: decrease HR
- Decrease conduction velocity
- Dilate BVs
- Decrease afterload
- Decrease oxygen demand
What are the three classes of CCBs? Specificities?
- Nifedipine and dihydropyridine: specific to BVs
- Diltiazem: specificity to BVs = heart
- Verapamil: cardiac specific
T/F: CCBs are first line drugs for treating CHF?
False
- Non-DHP CCB (Verapamil/Diltiazem) may reduce frequency of developing CHF among pts post-MI
- Non-DHP CCBs are negative inotropes and RELATIVELY CONTRAINDICATED in CHF pts
- DHP-CCB may increase rate of hospitalization for CHF c ompared o ther therapies (diuretics, ACEI, ARB) in primary prevention trials
- Amlodipine + placebo have some mortality among ischemic cardiomyopathy CHF pts
What are some common B1 and B2 adrenoreceptor antagonists?
- Cardioselective
- Partial agonists (ISA)
- Membrane stabilizing activity
- Acebutolol (QD)
- Atenolol (QD)
- Carvedilol (BID)
- Labetalol (BID)
- Metoprolol (BID)
- Propranolol (BID)
Cardioselective
- Acebutolol
- Atenolol
- Metoprolol
Partial agonsits (ISA)
- Acebutolol Membrane stabilizing activity
- Acebutolol
- Metoprolol
- Propranolol
How effective are beta blockers in CHF?
Acute effects in CHF:
- Can worsen CHF acutely!
- May be poorly tolerated initially
Chronic effects in CHF:
- Decreased mortality (better with carvedilol)
- Improved ejection fraction (EF)
- Improved quality of life
What are some angiotensin converting enzyme inhibitors (ACEIs)?
—pril
- Captopril (Capoten)
- Enalapril V(Asotec)
- Lisinopril (Zestril, Privinil) ….
What is the mechanism of action of ACEIs?
Prevent ACE from converting angI to angII
- Angiotensin II not able to vasoconstrict;; decreases afterload and increases CO
- Angiotensin II not able to promote aldosterone secretion, so decreases Na/water retention, decreases plasma volume, decreases preload, and decreases cardiac workload (may lead to edema and higher serum K)
Effectiveness of ACEIs in CHF therapy?
- Effect on mortality
- Physiologic benefit
- Outcomes
- Decreases mortality up to 40%
- Improves EF
- Improves exercise tolerance
- Improves quality of life
- Decreases hospitalizations
- Decreases cardiac size (remodeling)
What is the alternate pathway for ang II formation?
Angiotensinogen converted by:
- tPA
- Cathepsin G
- Tonin
into angiotensin II (bypass ACE step)
Clinical significance of alternate pathway is unknown
What are the different classes of angiotensin II receptors?
What do they do?
AT-1: sensitive to blockade by ARBs
AT-2: sensitive to blockade by CGP
Compare effects of AT1 and AT2 activation on:
- Growth
- Apoptosis
- Cell matrix
- BP
- Vasodilation
- NO production
Which receptor do ARBs block?
ARBs block AT1, thus AT2 effects dominate: inhibited growth, more apoptosis, decreased BP and more vasodilation and NO production
What is the effect of chronic anigotensin II levels?
What can be done?
Fibrosis of the heart
- Increased contractility and hypertrophy
- Increased fibrosis
- Decreased diastolic function
Treatment with ACEIs/ARBs will help reverse the fibrosis
What is the drug suffix for angiotensin II receptor blockers?
–sartan
When to use both ARB + ACE inhibitor in HF versus just one?
HF hospitalization: ARB + ACEI is better
All cause mortality: controversial; some studies said both ARB + ACEI while some said ACEI alone is better
What are the adverse effects of ACEIs?
- Dry and nonproductive cough due to elevated bradykinin levels
- Angioedema (swelling deep under the skin) also from bradykinin; serious complication (often switch to ARBs)
- Hypotension: monitor
- Hyperkalemia (opposite of diuretics): monitor
What are contraindications for ACEis and ARBs?
- Pregnancy/possible; crosses placental barrier and causes birth defects
- Renal failure
- Bilateral renal artery stenosis
What are some aldosterone antagonists used in CHF?
- Spironolactone
- Eplerenone
What is spironolactone?
Aldosterone agonist used in CHF
- Inhibits aldosterone-induced Na and water rentention by the kidney
- Inhibits fibrosis (heart)
- Decreases mortality in CHF pts (mechanism not completely understood)
What is Eplerenone?
Aldosterone agonist used in CHF
- Ephysus post-MI trial results show that it improves outcomes when added to standard therapy
Summary of CHF Therapies:
- Inotropes increase CO (mortality unaffected)
- Vasodilators decrease TPR/afterload (mortality unaffected)
- Diuretics decrease preload (mortality indeterminate)
- Beta-blockers decrease sudden death
- ACEIs decrease mortality and structural cardiac changes
- ARB decrease mortality and structural cardiac changes
- Aldosterone antagonists decrease mortality and morbidity
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Future CHF therapies
- Ca sensitizing agent: Levosimendan (increases contractility/CO without increasing MVO2)
- Neurohormonal/cytokine interdiction (endothelin and vasopressin receptor antags, soluble TNFa recep injections)
- Synchronized cardiac pacing therapy
- Autologous stem cell injections
- Gene therapy
Benefits of monotherapy vs. polytherapy?
As disease progresses, polytherapy is intiated
- Polytherapy is superior to montherapy
- Diboxin + diuretic + ACEI (pts receiving triple therapy are least likely to experience worsening of heart failure)
Random Habib interjection: diastolic dysfct
- What drugs for HCM
- What drugs for CHF (depressed LV function or RCM)
Diastolic dysfct treatment:
- Difficult to treat
- Therapy aimed at decreasing filling pressures of ventricle
- CCBs (esp Verapamil) used to improve diastolic properties in pts with HCM
- Diuretics + preload reducing agents (nitrates or ACEIs) used in pts with CHF and depressed LV function or RCM
Digoxin has a profound effect on myocyte intracellular concentrations of Na+, K+ and Ca2+. These effects are due to digoxin inhibiting:
A. Ca2+ ATPase of the sarcoplasmic reticulum
B. Na+/K+ ATPase of the myocyte cell membrane
C. Cardiac phosphodiesterase
D. Cardiac beta1 receptors
E. Juxtaglomerular renin release
Digoxin has a profound effect on myocyte intracellular concentrations of Na+, K+ and Ca2+. These effects are due to digoxin inhibiting:
A. Ca2+ ATPase of the sarcoplasmic reticulum
B. Na+/K+ ATPase of the myocyte cell membrane
C. Cardiac phosphodiesterase
D. Cardiac beta1 receptors
E. Juxtaglomerular renin release
A 58-year old man is admitted to the hospital with acute heart failure and pulmonary edema. Which of the following drugs would be most useful in treating pulmonary edema?
A. Digoxin
B. Dobutamine
C. Furosemide
D. Minoxidil
E. Spiranolactone
A 58-year old man is admitted to the hospital with acute heart failure and pulmonary edema. Which of the following drugs would be most useful in treating pulmonary edema?
A. Digoxin
B. Dobutamine
C. Furosemide
D. Minoxidil
E. Spiranolactone
- Furosemide is a loop diuretic (Lasix)
Compensatory increases in heart rate and renin release that occur in heart failure may be alleviated by which of the following drugs?
A. Milrinone
B. Digoxin
C. Dobutamine
D. Enalapril
E. Metaprolol
Compensatory increases in heart rate and renin release that occur in heart failure may be alleviated by which of the following drugs?
A. Milrinone
B. Digoxin
C. Dobutamine
D. Enalapril
E. Metaprolol
- Beta blocker
A 46-year old man is admitted to the emergency department. He has taken more than 90 digoxin tablets (0.25 mg each), ingesting them about 3 hours before admission. His pulse is 50-60 beats / minute and the electrocardiogram shows third degree heart block. His serum potassium is normal. Which one of the following is the most important therapy to initiate in this patient?
A. Digoxin immune Fab
B. Potassium salts
C. Lidocaine
D. Verapamil
E. Amiodarone
A 46-year old man is admitted to the emergency department. He has taken more than 90 digoxin tablets (0.25 mg each), ingesting them about 3 hours before admission. His pulse is 50-60 beats / minute and the electrocardiogram shows third degree heart block. His serum potassium is normal. Which one of the following is the most important therapy to initiate in this patient?
A. Digoxin immune Fab
B. Potassium salts
C. Lidocaine
D. Verapamil
E. Amiodarone
Which of the following drugs does NOT increase life span of pts with CHF?
A. Digoxin
B. Beta blockers
C. ARBs
D. Aldosterone blockers
E. ACE inhibitors
Which of the following drugs does NOT increase life span of pts with CHF?
A. Digoxin
B. Beta blockers
C. ARBs
D. Aldosterone blockers
E. ACE inhibitors
