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Flashcards in CHF 61/62 Deck (89):

Digoxin (Lanoxin)

Digitalis Glycoside
inotropic agent
(Digitoxin not available in US anymore)


Digoxin Immune Fab (DigiFab)

Digitalis Glycoside antidote

not a drug "per say" but goes in body and binds up digitalis (Digibind)



Non-Glycoside Inotropic Agent (± Vasodilator Activity)

synthetic β 1 -agonist (cardioselective) given
only IV in intensive care to treat severe, refractory congestive heart failure
causes increased CO mainly by increased ventricular β 1 -receptor action (positive inotropic effect)

tolerance can develop to all effects



Non-Glycoside Inotropic Agent (± Vasodilator Activity)

endogenous catecholamine given only IV in intensive care
to treat severe, refractory congestive heart failure.

positive inotropic effect due to direct activation of heart β1 receptors. Increases HR and oxygen demand more than dobutamine.
At certain doses (low to intermediate), can increase renal BF thru vasodilation, may enhance Na+, H2O excretion



Non-Glycoside Inotropic Agent (± Vasodilator Activity)

phosphodiesterase inhibitors



Non-Glycoside Inotropic Agent (± Vasodilator Activity)

phosphodiesterase inhibitors


Captopril (Capoten)

ACE inhibitor
NOT a prodrug


Enalapril (Vasotec)

ACE inhibitor
prodrug, needs *good liver function* (may be less predictable in CHF congestion)


Fosinopril (Monopril)

ACE inhibitor
prodrug, needs *good liver function* (may be less predictable in CHF congestion)


Quinapril (Accupril)

ACE inhibitor
prodrug, needs *good liver function* (may be less predictable in CHF congestion)


Losartan (Cozaar)



Valsartan (Diovan)



Candesartan (Atacand)



Hydrochlorothiazide (Microzide)



Furosemide (Lasix)



Epleronone (Inspra)



Spironolactone (Aldactone)




Direct Vasodilator
*Primarily Afterload Reduction*


Nitroprusside (Nitropress)

Direct Vasodilator
*Preload and Afterload Reduction*
raise IC cGMP-->vasodilation
IV only

SE: cyanide toxicity


Nitroglycerin (Minitran)

Direct Vasodilator
*Primarily Preload Reduction*


Isosorbide Dinitrate (Isosordil)

Direct Vasodilator
*Primarily Preload Reduction*


Nesiritide (Natrecor)

Direct Vasodilator
*Preload and Afterload Reduction + diuretic (natriuretic peptide)*
raise IC cGMP-->vasodilation of both arterial and venous sm. muscle
*promotes natriuresis*
IV only


Bisoprolol (Zebeta)



Carvedilol (Coreg)

antioxidant and alpha-blocker as well as a beta blocker


Metoprolol (Toprol-XL)



Conivaptan (Vaprisol) FYI

Vasopressin Antagonists (Vaptans)
V-1a and V-2 receptor antagonist approved for IV treatment for hospitalized pts with hyponatremia/excessive water retention


Tolvaptan (Samsca) FYI

Vasopressin Antagonists (Vaptans)
only a V-2 antagonist and is available orally for hyponatremia/water retention; often as an adjunct to standard diuretic therapy in CHF


CASE: 58 yr old man, SOB and weight gain

dyspnea on exertion after one flight of stairs, orthopnea, and ankle edema

nonproductive cough, nocturia (2-3 times/night) and more signs of edema.




Low Output or Congestive Heart Failure (CHF)

most common, gradual, typ. chronic (not acute like cardiogenic shock)
ventricles unable to pump out all the blood normally being returned to them because either they (1) fail to relax properly and fill with enough venous blood during diastole (*diastolic failure*) or (2) fail to contract with enough force during systole (*systolic failure*), or both. Either way SV (therefore CO) is reduced

blood back up-->systemic/pulmonary *congestive conditions*

*underperfused kidneys retain* large amounts of sodium and water which adds to the congestion

*LHF*(LV fails first) then RHF, almost always combined HF eventually (LHF most serious)


of Left Ventricular CHF (Also called Forward Failure)

*MI* (most common)
Coronary HD (atheroslerosis)
HTN related cardiac enlargement
LVH with inc. stiffness due to chronic primary HTN

less common: valvular disease, dilated cardiomyopathy, congenital heart diseases, cardiac infections and rheumatic heart disease.


s/s of LV CHF

respiratory wheezing ("cardiac asthma")-1st indication
nonproductive cough
rest dyspnea
Fatigue, Weakness and Exercise Intolerance
LVH and tachycardia (to compensate)


when considering drugs to tx LV CHF

determinants of CO
-contractility* where most problems lie


Ca2+ role in HF

increase in free IC Ca2+ for contraction
remove to relax

SR has powerful SR pump
allows contractile proteins to relax during diastole

can be stimulated by B-receptors: NE-->cAMP-->influx of Ca2+

contractile proteins impaired in CHF (cardiac musc. remodeling, assoc. with hypertrophy), do not get good strong contraction

also impairment of Ca2+ reuptake, not enough for during contraction

dec. B-receptors in membrane, so stimulation via NE is compromised (dec. due to high NE from sympathetic overaction


SV as a function of preload

Preload: filling force of venous blood returning to the ventricles
CHF pts: *high preload* (congested), but low output (SV, CO) due to decreased ventricular performance

suppressed output-->congestion in lungs, diff breathing, fatigue

mechanism of digoxin is to raise curve to try to bring up to normal (output)


SV as function of afterload

no compromise in HTN pts
CHF: SV (and CO) decreases dramatically as afterload increases
to compensate for low CO, inc. SNA and Ang II levels, which inc. PVR-->FURTHER increasing afterload

meds to dec. afterload


CO as function of HR

hill, CO increases with increased HR to a point
w. extremely high HR, compromise CO

in CHF: body raises HR as a compensatory mechanism (involves compensatory changes in both SNA and PNA neural traffic to the SA node). Therefore, tachycardia is a common observation in CHF.

meds to bring down high rates


hypertrophy in HF is ??

inward, also heart stiffens, leads to even more failure


effects of SNS on CO determinants

SNS: compensates by stimulating ventricles to inc. contractility until B-rec down regulate and dec. NE stored and SNS not enough to have positive effect on contractility (more down reg in ventricles, not much in SA node)
also responsible for inc. in HR
SNS constriction: partly responsible for increases in preload, afterload, cold extremities and pallor generally seen in CHF.

also PNS: vagal withdrawal will inc. HR


effects of RAAS in CO

increase in Ang: inc. vasoconstriction, inc. TPR, inc. afterload
raise aldo: inc. Na+, water retention, inc. preload

cardiac remodeling:
AngII can contribute to hypertrophy
aldo can contribute to stiffening


Digitalis Glycosides

most important actions: *increase myocardial contractions and decreased HR*

directly increase the intrinsic force of myocardial contraction (a positive inotropic action)
typically add-on drugs


Digitalis Glycosides: Mechanisms of Increased Myocardial Contractility

*directly inhibit cell membrane bound Na+, K+-activated ATPase (Na+-, K+- ATPase)*. Inhibition of this Na/K exchanger (also called the Na pump) reduces the transport of Na+ out of the cell resulting in an increased intracellular concentration of free Na+; [Na+]i . The increased intracellular [Na+]i in turn reduces the normal transport of Ca++ out of the cell via the Na/Ca exchanger. This causes *increased intracellular free Ca++; [Ca2+]i* Thus, more Ca++ for contraction, both immediately and after its storage and subsequent release from the sarcoplasmic reticulum (SR)

*increased intracellular free Ca++* is then responsible for the increased myocardial contractility after digitalis glycosides.


digitalis glycosides cause the following CV changes to occur in a patient with CHF:

increase in CO *almost immediately*
Some increased excretion of accumulated salt and water, thus diuresis and mobilization of edematous fluid, as a result of improved renal perfusion (eventually)
Some reversal in SNS-induced reflex tachycardia and arteriolar and
venous constrictions. (better B-receptor function)


digitalis glycoside mech: inhibits Na+/K+ ATPase-->buildup of IC Na+, will inhibit ??

Na+/Ca2+ exchanger, so Ca2+ stays in cell, inc. contractions
useful for stimulating better systolic contraction


digitalis glycoside effects

better perfusion of kidneys
edema drops
decrease preload
reversal of high SNS
better B-receptor function
reduce HR (something els involved)


high HR decreased by

reduction of SNS
AND a vagal (parasympathetic) effect and an extravagal effect

*digitalis glycosides are usually not recommended just to slow the heart in normal sinus tachycardia, if there is no accompanying CHF (better drugs to do this) main mech is to inc. CO, thereby increase time allowed for diastolic filling (which may further ↑ CO).


Vagal slowing:

Extravagal slowing:

central vagal stimulation plus sensitization of receptors at related autonomic ganglia (nicotinic) and cardiac sites (muscarinic), and possibly carotid baroreceptors.

“Extravagal” slowing of cardiac rate comes at higher doses and may involve lengthening of the effective refractory period and decreased conduction velocity of electrical activity (action potentials) in AV-node.


digitoxin vs digoxin

digitoxin has higher values chart pg. 11

digitoxin has high therapeutic plasma levels, close to toxic plasma levels!! (low margin of safety)

renal excretion: digoxin
hepatic metabolism: digitoxin


digitalis toxicity

low margin of safety

manifest toxicity on virtually all systems likely (though not exclusively) due to too much inhibition of Na/K-ATPase: calcium overload.

anorexia, N/V/D


digitalis CV SEs

Every known type of clinical arrhythmia: abnormal bradycardia, paroxysmal atrial tachycardia, Vtach, a fib


digitalis CNS effects

Headache, fatigue, drowsiness.

Mental disorientation, confusion, delirium ("digitalis delirium"), convulsion


digitalis vision effects

Blurred vision,
White borders or halos on dark objects.


Digoxin Antibodies: Digoxin Immune Fab (DigiFab)

bind to the molecules of Digoxin (or Digitoxin) and the resulting Fab- Fragment-Digitalis complex is excreted in the urine
for life-threatening digitalis glycoside toxicity and/or OD characterized by severe hyperkalemia presumably due to loss of IC potassium (so raising serum K further would most likely not work and may cause other cardiac problems)


digitalis toxicity

low margin of safety

manifest toxicity on virtually all systems likely (though not exclusively) due to too much inhibition of Na/K-ATPase: calcium overload.

GI effects: anorexia, N/V/D


digitalis toxicity CV SEs

Every known type of clinical arrhythmia: abnormal bradycardia, paroxysmal atrial tachycardia, Vtach, a fib


digitalis toxicity CNS effects

Headache, fatigue, drowsiness.

*Mental disorientation*, confusion, *delirium ("digitalis delirium")*, convulsion


digitalis vision effects

*Blurred vision,
White borders or halos on dark objects*


tx of digitalis toxicity

monitor Plasma glycoside drug levels
Discontinue the glycoside or decrease its dose
discontinue or decrease diuretics if serum K is too low
administer K+ chloride orally or I.V.
(infusion, NOT bolus injection) (and not if serum K+ is already high)
Digoxin Antibodies
FA: also; cardiac pacer, Mg2+


Digoxin Antibodies: Digoxin Immune Fab (DigiFab)

bind to the molecules of Digoxin (or Digitoxin) and the resulting Fab- Fragment-Digitalis complex is excreted in the urine
for life-threatening digitalis glycoside toxicity and/or OD characterized by severe hyperkalemia presumably due to loss of intracellular K+?(so raising serum K further would most likely not work and may cause other cardiac problems)


Non-Glycoside Inotropic Agents (+/- Vasodilator Activity)

reserved for hospitalized pts refractory to HF
given IV
stimulate B1 receptors on cell membrane

will increase O2 demand


Non-Glycoside Inotropic Agents (+/- Vasodilator Activity) SEs

tolerance may develop
(also tolerance to inc. O2 demand-good!)


dopamine SEs

Reputation diminished due to side effects (more than dobutamine) and sometimes lack of demonstrable effectiveness.

Tolerance can develop to all cardiac effects.


dobutamine SEs

some tachycardia and increase in cardiac oxygen demand and arrhythmia though not as much as other β-agonists might do


PDE inhibitors: inhibit degradation of cAMP in order to overcome tolerance due to

down regulation of B receptors

production of cAMP is a facilatory process, always basal level regardless of B-receptor function


phosphodiesterase inhibitors

used IV for treatment of severe, refractory CHF cases or after tolerance develops to the abovementioned beta-agonists.
positive inotropic mechanism involves inhibition of cAMP inactivation
*increased free Ca availability to contractile proteins during systole*. Also improve diastolic relaxation (filling) by stimulating more SR Ca2+ uptake during diastole
little or no tolerance develops during their use and their cardiac effects are not highly dependent on the presence of adequate numbers of beta receptors in cardiac muscle cell membranes
peripheral vasodilator effects (helps relieve CHF symptoms)


PDE inhibitor SEs

Thrombocytopenia (inamrinone only).
Increased myocardial oxygen demand (from the positive inotropic action) may be fatal in patients with ischemic heart disease (because no tolerance develops).


ACE inhibitors

can correct RAAS induced problems: dec. preload and after load
do not significantly raise HR

-reduces K+ wasting of RAAS/other diuretics, good if using digitalis (hypokalemia may increase dig. toxicity)
-may reduce high aldosterone-related myocardial fibrosis (ventricular stiffness)
-inhibit ACE-dependent production of AngII right in the myocardial tissue which is thought to contribute to hypertrophy in CHF


ACE inhibitor SEs

non-productive cough (buildup of bradykinin (good for lowering BP)
how to avoid? switch to ARB, don't inhibit ACE but block AngII receptors


ACE inhibitor drug interactions

Too much reduction in arterial BP when combo with diuretics and other antihypertensive agents (e.g. direct vasodilators)


"ACE-escape pathway"

AngII produced independent of ACE

ACE inhibitors do not help here, ARBs do!!



Competitive antagonists of A-II at the level of the A-II-receptor subtype 1 (which is main subtype in heart)

Do not cause as much ACE inhibitor related cough presumably because it does not cause high levels of bradykinin.

In the heart, AngII production (contributes to hypertrophy in CHF) is both ACE-dependent AND ACE-independent. ARBs may thus better inhibit AngII contribution to the cardiac hypertrophy than ACE inhibitors. [Some say as much as 40% of all A-II is produced by ACE-independent pathways; “ACE escape” phenomenon].



*marked retention of sodium and H2O, reduce congestive symptoms
*reduce preload and peripheral edema
K+ sparing drugs limited to aldosterone antagonist because of high aldo, important to give to maintain serum K+ levels (decrease dig. toxicity)


CHF pts may have v. low GFR (i.e. less than 30 ml/min) so need to use ??

loop diuretics, otherwise use thiazides


another benefit of K+ sparing aldosterone antagonists

reduces aldosterone which contributes to stiffening of heart muscle


Direct Vasodilators

will dilate no matter what causes the constriction (AngII, NE, vasopressin, (all may be inc. in HF))
*reduce afterload*
*reduce preload* (via venodilation)

most given IV to hospitalized pts, refractory to other tx
also right after acute MI, who had preexisting chronic CHF

all likely to reflexively inc. in HR


Direct Vasodilators SEs

all likely to reflexively inc. in HR

nitro and isosorbide denigrate: tolerance may develop (to reduce: use daytime tx, but not at night)

Nitroprusside and nesiritide: *very rapid action*: may lower BP too much (also only given IV, only intensive care)



fewer post-MI pts put on B-blockers developed CHF (counterintuitive?)

*protect B-receptors from downregulation in ventricles*, continue to provide adequate SNS
preventing excessive tachycardia and arrhythmias
*inhibit renin release, inhibit RAAS*

start with safe, low dose
however, do not start B-blocker late stage HF when already sev. down regulated B-receptors


Invabradine can be added to B-blockers FYI

inhibits funny current


B-blocker dosing

Start with safe, low doses since high doses could acutely block whatever supportive effects high endogenous catecholamines may have in some patients and thus immediately worsen their failure



for pts refractory to other tx, *hyponatremic*, super elevated vasopressin (ADH) *extreme H2O retention*

vaptans reduce these effects!
also for SIADH (excessive ADH--> excess water retention)

do NOT reduce mortality


diuretic action of digitalis glycosides

can produce copious urine output in patients with CHF. Yet, they are not diuretics in the conventional sense. They have no notable direct effect on the renal tubules, at least at therapeutic doses.

secondary consequence of improved hemodynamics due to cardiac actions (only have diuretic action if used successfully in CHF pts)


Digitalis glycoside action flow chart

inhibition of Na/K exchange-->increase intracellular Na+--->decreased Na/Ca exchange-->increased intracellular Ca2+-->increased contraction


digitalis glycoside drug interactions

*Phenylbutazone* displaces digitoxin from that bound to plasma protein causing high free serum levels of the glycoside.
*Phenobarbital and Phenytoin* are likely to decrease the plasma levels and t1⁄2 of digitoxin by hastening its hepatic metabolism through induction of hepatic microsomal enzymes.
*Quinidine* increases serum levels of digoxin by displacing it from binding sites in skeletal muscle or by inhibiting its renal clearance. *Verapamil* may also inhibit its renal clearance.
Bioavailability of Digoxin is reduced by antacids gels, *Sulfasalazine* and bile acid binding resins (e.g. *Cholestyramine*)

Renal diseases increase digoxin half-life; hepatic disease increase digitoxin half-life and hypothyroidism increases both.


Oral digitalization: 2 methods

1. administer a "first day" loading dose followed by a daily maintenance dose

2. give ONLY a maintenance dose each day and waiting for the patient to become fully digitalized over a longer period. This method is safer and may be
preferred in many cases.


Loading "digitalizing" dose

amount of the digitalis glycoside necessary to rapidly bring the body stores to an effective level on the 1st day. This loading Dose may consist of a rather large initial dose followed by smaller (supplemental) doses throughout the 1st day.


digitalis maintenance dose

amount of the digitalis glycoside lost from the body in 24 hours (once an effective dosing schedule is achieved) which must be replaced once daily.


Plasma calcium and digitalis glycosides are ??

synergistic with respect to toxicity. Thus, a sudden increase in serum calcium can initiate arrhythmias in a digitalized patient. Removal of Ca++ from the plasma decreases digitalis glycoside toxicity.


Plasma potassium and digitalis glycosides are ??

antagonistic (one reason may be that they compete for binding to the same extracellular site on the Na pump). Thus, in patients with digitalis intoxication, raising serum potassium levels tends to alleviate the toxic symptoms and lowering K can do the opposite. In fact, administration of K+ is one form of treatment of digitalis intoxication.


these two factors can both increase digitalis toxicity

acid-base imbalance and low plasma Mg+


Two antiarrhythmic drugs which may be of value in rapidly counteracting the most serious arrhythmic aspects of digitalis toxicity:

Lidocaine and Propranolol.