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Pharmacology > Heart Failure > Flashcards

Heart Failure Flashcards

1
Q

Describe the compensatory changes in heart failure?

A
  1. HR: An increase is first compensatory mechanism seen in HF (extrinsic, mediated via baroreceptor response to decreased CO → resulting in increased SNS activity)
  2. Afterload (resistance against which heart must pump blood): Increased in HF due to reflex increase in SVR (extrinsic, mediated through increased SNS activity)
  3. Preload (stretch of myocardial cell prior to contraction): Usually increased in HF due to increased BV (extrinsic, mediated via activation of RAAS) and increased venous tone (extrinsic, via activation of SNS)
  4. Ventricular hypertrophy (myocardial remodeling): Most important INTRINSIC compensatory mechanism resulting in an increase in muscle mass that helps maintain function initially but chronically contributes to a downward spiral in cardiac function
  5. Natriuretic Peptides: “Beneficial” hormones secreted in response to increased filling pressures. ANP is released from atrial cells in response to atrial distention and via specific receptors enhances Na+ and water excretion, vasodilation, block of renin release and AngII effects on aldosterone release. BNP is released in HF and a close relationship has been found between serum BNP levels and clinical severity of HF.
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2
Q

Acute and Chronic effects of compensatory responses- SNS and RAAS activation

A
  1. Acute benefits of preservation of blood pressure and blood flow
  2. Chronic progression of heart failure from increased cardiac workload and metabolic demands, ventricular hypertrophy and dilatation, and myocardial damage / fibrosis
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3
Q

What are the specific goals of HF managment

A
  1. reduction of congestion- fluid optimization w/ diuretics
  2. modulate neurohormonal activation resulting in long-term stabilization, positive remodeling, and increased survival with RAAS antagonist and BB
  3. improve flow- may be difficult to accomplish pharmacotherapeutically with vasodillators and requires mechanical devices or transplant
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4
Q

What drugs for HF are used to improve symptoms only

A
  1. digoxin
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5
Q

What drugs for HF are used to improve sx AND prolong patient survival?

A
  1. diuretics
  2. BB
  3. ACEI
  4. ARBs
  5. aldosterone antagonists
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6
Q

What drugs for HF are used to prolong survival?

A

hydralazine (decrease afterload) + nitrates (decrease preload)

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7
Q

Describe how drugs are prescribed with new onset HF

A
  1. new dx–> start ACEI (if cannot tolerate ACEI due to cough start ARBs)
    - start diuretic for congestive sx and fluid retention
  2. Add BB and titrate up to max dose tolerated
  3. add spironlactone if pt remains sx despite other drugs

**Add digoxin at any time if pt is in NSR and symptomatic despite tx w/ diuretic, ACEI (or ARBs) and BB OR if pt is in Afib then use as first line therapy

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8
Q

How can diuretics help in HF

A
  1. reverse Na+ and Fluid retention

2. relieve volume overload : dyspnea-peripheral edema

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9
Q

Why are loop diuretics preferred with HF

A
  • bc of efficacy to augment w/ a thiazide diuretic

- can be used chronically and acutely

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10
Q

___ diuretic is commonly used, but some patients respond better to___ or ___ due to better and more reliable absorption

A

Furosemide

torsemide

bumetanide

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11
Q

How do ACEIs help in HF

A
  1. Produce vasodilation (reduce preload) and ↓ aldosterone activation
  2. Plus antiremodeling effect

*start at low dose and titrate to goal

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12
Q

How can ARBs help in HF

A
  1. used in pts intolerance to ACEI (ie. cough)

* no apparent benefit from dual therapy with ACEI and ARBs

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13
Q

How can Sacubitril as combination with ARB valsartan (Entersto) help with HF

A
  1. used in HFrEF- role evolving, may be considered in place of ACEI for initial therapy in certain HF pts
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14
Q

describe the mechanism of action of Neprilysin inhibitor?

A

Neprilysin is an endopeptidase that degrades various vasoactive peptides (ANP-BNP, bradykinin, adrenomedullin). By increasing levels of these peptides neprilysin decreases vasoconstriction, sodium retention, and deleterious cardiac remodeling.

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15
Q

Describe the adverse effects /DDI of Neprilysin inhibitors

A
  1. hypotenion ad hyperkalemia
  2. cough (less than ACEI though)
  3. hyperkalemia w/ concurrent use of potassium-sparing diuretics
  4. worsening of renal fxn if taken with NSAIDs
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16
Q

How do BB help with HF

A
  1. Antagonizes effect of SNS plus antiremodeling effect
  2.   Relative to ACE inhibitors, may exacerbate heart failure inshort run and benefits are delayed
  3. BUT long-term improvements in LV function and survival are dose-dependent
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17
Q

What BB are used in HF

A

Carvedilol (non-selective, B1 and B2)

Metoprolol (B1 selective)

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18
Q

Beta-blockers improve cardiac function in heart failure by:

A

decreasing cardiac remodeling

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19
Q

When are aldosterone antagonists used in HF

A
  1. Added to therapy for LVEF less than 30% optimized on ACEI/ARB and β-blocker therapy
  2. Blocks aldosterone effect on kidney
    -   ACEI / ARB aldosterone block is incomplete
    -   Produces additional Na+ loss plus antiremodeling
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20
Q

What do you need to monitor closely when taking an aldosterone antagonsit?

A

Carefully monitor serum K+ (less than 5.0) and renal function (GFR over 30 ml/min)

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21
Q

What aldosterone antagonists is most commonly used in HF

A

spironolactone

-eplerenone can be used if endocrine side effects (gynocomastea)

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22
Q

Describe the beneficial effect of spironolactone in HF:

A

blocks cardiac hypertrophy

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23
Q

When are vasodilators added to HF therapy?

A

Added to therapy for patients with persistent symptoms

  1.   Therapy with an ACEI and a beta-blocker ineffective or patients intolerant to both ACEI-ARBs
  2.   Particularly effective in blacks in NYHA class III-IV
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24
Q

How are vasodilators beneficial in HF

A

Produces arterial dilation which:

  1. decrease in afterload
  2. reduce cardiac work
  3. less MR
  4. venous vasodilation (decrease preload)
25
Q

What vasodilators are used in HF

A

Hydralazine plus isosorbide dinitrate

26
Q

When is digoxin used in HF

A
  1. Added for systolic dysfunction to control symptoms (fatigue, dyspnea, exercise intolerance) in NYHA (II)-III-IV patients and for HF with atrial fibrillation to control the ventricular rate
27
Q

Survival benefits if serum digoxin level between ___ ng/ml – worsen if ___

A

0.5-0.8ng/ml

over 1.2 ng/ml

28
Q

Describe the mechanism of digoxin

A
  1. Inhibition of membrane Na+-K+ ATPase enzyme on myocardial cell membrane
  2. intracellular Na increases as a result and diminishes the gradient for Ca++ extrusion from the cell via Na+/Ca++ exchanger
  3. Thus, intracellular Ca++ remains elevated allowing more to be sequestered in the sarcoplasmic reticulum (SR)
  4. The increased Ca++ in SR stores leads to increases in the contractile force when released by “trigger” Ca++ entering through the L-type Ca++ channel.
29
Q

What are the INDIRECT electrophysiologic effects of digoxin

A
  1. parasympathomimetic via stimulation of vagal nerve
    - slows HR at SA node
    - decrease AV node conduction velocity
  2. sensitzation of baroreceptors
    - reduce sympathetic outflow
    - reverse desensitization that occurs in HF
    - effect occurs at lower Cp than positive inotropic effect
30
Q

What are the DIRECT electrophysiological effects of digoxin?

A

(membrane potential effects)
1. increase abnormal automaticity via resting depolarization (Na+-K+-ATPase can’t maintain Em) and oscillatory depolarizations (intracellular Ca++ overload and Ca++-dependent afterpotentials) that predispose the patient to arrhythmias (PVCs → ventricular tachycardia → ventricular fibrillation).

  • This action of digoxin is additive with epinephrine and increases the pro-arrhythmic potential of each drug.
31
Q

What can occur with digoxin + epi?

A

Ca++ overload–> PVCs–> V tach–> Vfib

32
Q

describe the absorption and distribution of digoxin

A

Absorption: Fairly well absorbed - bioavailability of tablets is unreliable

Distribution -Widely distributed, taken-up avidly by heart, kidney, liver, and
skeletal muscle

33
Q

Describe the metabolism/excretion of digoxin

A
  1. not extensively metabolized (some by bacteria)

2. excreted unchanged by KIDNEYS (dosage must be reduce for pts w/ renal failure)

34
Q

___ is only approved oral inotrope.

A

Digoxin

35
Q

Digoxin provides ___ relief only and leads to a significant reduction in hospitalizations but has little effect on overall mortality (increased mortality from cardiac arrhythmias) unless special care to keep digoxin plasma levels at low end of therapeutic range [0.5-0.8 ng/ml]

A

symptomatic

36
Q

Digoxin produces ___ effect (moderate but persistent) BUT beneficial effects on survival are more likely to the ____ that occurs at lower plasma levels. This action decreases the abnormally high compensatory sympathetic outflow, reducing heart rate, venous tone with decreased heart size and oxygen demand

A

positive inotropic

baroreceptor sensitization

37
Q

baroreceptor sensitization from digoxin decreases:

A
  1. the abnormally high compensatory sympathetic outflow,
  2. reducing heart rate,
  3. venous tone with decreased heart size and
  4. oxygen demand
38
Q

Why does hypokalemia predispose you to toxicity with digoxin?

A

Increased binding of digoxin to Na+-K+-ATPase (less competition w / K+ for binding) and facilitation of abnormal cardiac automaticity.

*K+ and digoxin compete for the same site so hypo-K+ + digoxin = digoxin toxicity

39
Q

what are some side effects from digoxin toxicity

A
  1. GI: both direct [large oral doses] and CNS effects [stimulation of chemoreceptor trigger zone (CTZ)]: nausea, anorexia, vomiting, diarrhea.
  2. CNS: vagal and CTZ stimulation (vomiting), disorientation, hallucinations, visual disturbances (aberrations of color perception, yellow halo).
  3. endocrine: Gynecomastia / galactorrhea seen rarely in men; due to peripheral estrogenic action or hypothalamic stimulation
40
Q

How do you treat GI disturbances caused from digoxin toxicity?

A

Generally sufficient to withhold drug. Most common sign in adults

41
Q

How do you treat cardiac arrhtymias (bradycardia) caused from digoxin toxicity?

A

Monitor serum K+ and EKG and correct electrolyte imbalance (oral K+ supplements)

42
Q

How do you treat more serious cardiac arrhythmias (won’t respond to K+) caused from digoxin toxicity?

A

PVCs–> PSVT

Administer parenteral K+ and monitor EKG, treat with antiarrhythmic agents (lidocaine [does not enhance AV block], phenytoin, propranolol)

43
Q

How do you treat very serious intoxication (suicidal overdose) caused by digoxin toxicity?

A

produces heart block

Serum K+ already high, antiarrhythmics may lead to cardiac arrest - best to treat with digoxin antibodies (Digibind®)

44
Q

What are some drugs that cause DDI w/ digoxin

A
  1. Diuretics, Amphotericin B
  2. Quinidine-verapamil-nifedipine
  3. Epi
  4. macrolides (azithromyocin-clarithomycin)
45
Q

How does diuretics, amphotericin B interact w/ digoxin and what is the tx

A

drug-induced hypokalemia
can predispose to digoxin toxicities

Tx: check K+

46
Q

How does Quinidine-verapamil-nifedipine interact w/ digoxin and what is the tx

A

Displace digoxin from
tissue sites plus ↓ renal clearance –> ↑ digoxin levels

**displacements may also be seen with NSAIDs, amiodarone

Tx: need to reduce digoxin dose

47
Q

How does epi interact w/ digoxin and what is the tx

A

Sensitizes heart to digitalis-induced arrhythmias via ↑ intracellular Ca++

tx: use cautiously

48
Q

What is the DDI with macrolides and digoxin and how do you tx it?

A

May reduce intestinal bacteria that metabolize portion of digoxin dose leading to increased digoxin levels.

tx: Need to reduce digoxin dose.

49
Q

What is the mechanism of action of Milrinone (Primacor)

A
  • Increase myocardial contractility by alteration of Ca++ flux through inhibition of phosphodiesterase (increased cAMP levels → increased Ca++ influx) and not via Na+-K+-ATPase inhibition or beta-adrenergic receptor effect).
  • Increase in cAMP levels in vascular tissue results in vasodilation beneficial in heart failure so these are known as “inodilators”.
50
Q

what are toxicities associated with Milrinone (Primacor)

A
  1. Ventricular and supraventricular arrhythmias,
  2. nausea / vomiting,
  3. thrombocytopenia
51
Q

What are benefits of Milrinone (Primacor)

A

acute: pharmacotherapeutic bridge to transplant

Long-term: uncertain (have NOT been shown to decrease mortality probably due to increased risks of
arrhythmias and may actually increase mortality).

52
Q

What kind of drug is Milrinone (primacor)

A

phosphodiesterase inhibitor

53
Q

Describe how phosphodiesterase inhibitors and B1 agonist work

A
  1. binding of B1 agonist (dopamine, dobutamine) activates adenylyl cyclase, which produces cAMP
  2. cAMP activates PK which then phosphorylates a Ca channel
  3. phosphorylation of a Ca channel increases Ca flow into the cell, causing increased force of contraction of heart muscle
  4. Phsophodiesterase inhibitors prevent hydrolysis of cAMP and thus prolong the action of PK===> increase contractility
54
Q

What class of drugs are used to reduce fluid retention in HF

A

diuretics

55
Q

What class of drugs are used to reduce preload in HF

A

ACEI

nitrates

56
Q

What class of drugs are used to reduce afterload in HF

A

ACEI
hydralazine
minoxidil

57
Q

What class of drugs are used to reduce remodeling and/or arrhythmia in HF

A

BB
aldosterone antagonists
ACEIs

58
Q

What class of drugs are used to increase contractility in HF

A

digoxin

Pharmacology (31 decks)

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