Heart Failure

Question 1

Heart failure is

Answer 1

a complex, progressive disorder in which the heart is unable to pump sufficient blood to meet the needs of the body.

Question 2

Heart failure cardinal symptoms are:

Answer 2

1- dyspnea
2- fatigue
3- and fluid retention

Question 3

Underlying Causes include:

Answer 3

arteriosclerotic heart disease
MI
hypertensive heart disease
valvular heart disease, dilated cardiomyopathy
congenital heart disease

Question 4

Goals of pharmacologic intervention in HF

Answer 4

1- Alleviate symptoms
2- slow disease progression
3- and improve survival.

Question 5

Beneficial effects of pharmacologic intervention include:

Answer 5

1-reduced myocardial work load,
2- decreased extracellular fluid volume,
3- improved cardiac contractility,
4- and a reduced rate of cardiac remodeling.

Question 6

What happen to contraction if we increase intracellular calcium levels (or that increase the sensitivity of the contractile machinery to calcium) ?

Answer 6

increase the force of contraction (inotropic effect).

Question 7

Compensatory physiological responses in HF

Answer 7

1- increase Venous Pressure
2- Due to reduced cardiac output the body will
A- Increase Sympathetic Activity (Baroreceptors sense a decrease in BP and stimulates β1 & α1 -receptors)
This results in an increased HR and force of contraction. Vasoconstriction enhances venous return and increases cardiac preload.
These responses increase the work of the
heart,
B- ↑Renin ↑Aldosterone ↑sodium and water retention
3-Natruretic Peptide (causing Vasodilation)

Question 8

Activation of the RAAS:
A fall in CO cause what is the Compensatory action in RAAS ?

Answer 8

decreases blood flow to the kidney
prompting the release of renin, and resulting in increase angiotensin II and release of aldosterone.

Blood volume increases and more blood is returned to the heart.

Question 8

Activation of the RAAS:
If the heart is unable to pump the extra volume what happen to venous pressure ?

Answer 8

venous pressure increases and peripheral edema and pulmonary edema occur.

Question 9

Activation of the RAAS:
These compensatory responses increase the work of the heart and can contribute to further decline in cardiac function

Answer 9

True

Question 10

Activation of natriuretic peptides

Answer 10

An increase in preload also increases the release of natriuretic peptides

Question 10

Natriuretic peptides, which include:
and which ones the most important ?

Answer 10

atrial, B-type, and C-type

atrial and B-type natriuretic peptides are the most important.

Question 11

Activation of the natriuretic peptides ultimately results in:

Answer 11

◼ vasodilation
◼ natriuresis
◼ inhibition of renin and aldosterone release
◼ and a reduction in myocardial fibrosis
◼ This beneficial response may improve cardiac function and HF symptoms.

Question 12

Myocardial hypertrophy:

Answer 12

stretching of the heart muscle leads to a stronger contraction
Excessive elongation of the fibers results in weaker contractions and a diminished ability to eject blood

Question 13

Type of Failure in Myocardial hypertrophy ?

Answer 13

1- systolic failure” or HF with reduced ejection fraction (HFrEF) and is the result of the ventricle being unable to pump effectively

2- Patients with HF may have “diastolic dysfunction,” a term applied when the ability of the ventricles to relax and accept blood is impaired by structural changes such as hypertrophy

The thickening of the ventricular wall and subsequent decrease in ventricular volume decrease the ability of heart muscle to relax.

In this case, the ventricle does not fill adequately, and the inadequacy of cardiac output is termed “diastolic HF” or HF with preserved ejection fraction (HFpEF).
◼ Diastolic dysfunction, in its pure form, is characterized by signs and symptoms of HF in the presence of a normal functioning left ventricle. However, both systolic and diastolic dysfunction commonly coexist in HF

Question 14

If the compensatory mechanisms adequately
restore CO, HF is said to be compensated
If the compensatory mechanisms fail to maintain CO, HF is

Answer 14

decompensated and the patient develops worsening HF signs and symptoms.

Question 15

Acute (decompensated) HF Sign and Symptoms :

Answer 15

◼ Typical HF sighs and symptoms include:
◼ dyspnea on exertion,
◼ orthopnea,
◼ paroxysmal nocturnal dyspnea,
◼ fatigue, and peripheral edema.

Question 16

Chronic HF is typically managed by:

Answer 16

◼ fluid limitations (less than 1.5 to 2 L);
◼ low dietary intake of Na (<2000 mg/d);
◼ treatment of comorbid conditions;
◼ and use of diuretics.

Question 17

◼ Specifically for HFrEF:

Answer 17

◼ inhibitors of the RAAS,
◼ inhibitors of the sympathetic nervous system,
◼ and drugs that enhance activity of natriuretic peptides have been shown to improve survival and reduce symptoms.

Question 18

Could we use Inotropic agents for acute HF

Answer 18

yes , are reserved for acute signs and symptoms of HF and are used mostly in the inpatient setting.

Question 19

Drugs that may precipitate or exacerbate HF.(should be avoided if possible.) ?

Answer 19

NSAIDs,
alcohol,
Non dihydropyridine CCBs
and some antiarrhythmic drugs,

Question 20

The compensatory activation of the RAAS in HF leads to

Answer 20

increased workload on the heart and a resultant decline in cardiac function.

Question 21

inhibition of the RAAS is an important pharmacological target in the management of HF.

ACE-inhibitors are a part of standard pharmacotherapy in HFrEF. By :

Answer 21

↓ Output of sympathetic
↓Retention of water and Sodium
↑ Vasodilation
↑ Bradykinin level
↓ (Lead to)
Decrease preload and afterload

Question 22

Therapeutic use:
ACE inhibitors may be considered for patients with (asymptomatic or symptomatic) ?
and which Ventricular ?
Dose ?
For HTN , MI ?

Answer 22

asymptomatic and symptomatic HFrEF.
For All

ACE inhibitors are indicated for patients with all stages of left ventricular failure.

These agents should be started at low doses and titrated to target or maximally tolerated doses in the management of HFrEF.

◼ ACE inhibitors are also used in the treatment of HTN.

◼ Patients who have had a recent MI or are at high risk for acardiovascular event also benefit from long-term ACE inhibitor therapy

Question 23

Angiotensin-receptor blockers Antagonist for which Angiotensin Receptor ? Why it's better than ACE inhibitor ? Actions ?

Answer 23

ARBs orally active compounds that are extremely potent competitive antagonists of the AT1 receptor. Because ACE inhibitors inhibit only one enzyme responsible for the production of angiotensin II, ARBs have the advantage of more complete blockade of the actions of angiotensin II. Their use in HF is as a substitute for ACE inhibitors in those patients with severe cough or angioedema.

Question 24

Aldosterone Antagonists Patients with HF have elevated levels of ? Drugs and their effects ? Aldosterone antagonists are indicated in patients with?

Answer 24

of aldosterone due to angiotensin II stimulation and reduced hepatic clearance of the hormone. Spironolactone and eplerenone are antagonist of aldosterone, thereby preventing salt retention, myocardial hypertrophy, and hypokalemia. ◼ Spironolactone also has affinity for androgen and progesterone receptors, and is associated with endocrine-related adverse effects such as gynecomastia and dysmenorrhea. symptomatic HFrEF or HFrEF and recent MI

Question 25

β-Blockers The benefit of β-blockers is ? Three β-blockers have shown benefit in HFrEF: ? β-Blockers are recommended for all patients with chronic, stable HFrEF or Acute . ? Dose ? Which B-blocker are metabolized by CYP2D6 ? carvedilol is a substrate of P-glycoprotein (P-gp).so what happen if we take carvedilol with P-gp Inhibitor ? β-Blockers should be used with caution with other drugs that?

Answer 25

their ability to prevent the changes that occur because of the chronic activation of the sympathetic nervous system. bisoprolol, carvedilol, and metoprolol. chronic, stable HFrEF Treatment should be started at low doses and gradually titrated to target doses based on patient tolerance and vital signs Both carvedilol and metoprolol Increased effects of carvedilol may occur if it is coadministered with P-gp inhibitors. slow AV conduction, such as amiodarone, verapamil, and diltiazem

Question 26

Diuretics What the effect of body volume ? (reduce what signs and symptoms ? Afterload , preload ?

Answer 26

Diuretics reduce signs and symptoms of volume overload, such as dyspnea on exertion, orthopnea, and peripheral edema. ◼ Diuretics decrease plasma volume and, subsequently, decrease venous return to the heart (preload). This decreases cardiac workload and oxygen demand ◼ Diuretics may also decrease afterload by reducing plasma volume, thereby decreasing BP.

Question 27

the most commonly used diuretics in HF ? Why ?

Answer 27

Loop diuretics, due to extensive diuresis effect and those with renal insufficiency

Question 28

True or False Since diuretics have not been shown to improve survival in HF, they should only be used to treat signs and symptoms of volume excess

Answer 28

True

Question 29

Angiotensin Receptor–Neprilysin Inhibitor Neprilysin is the enzyme responsible ? We use it with ARB or ACE ?

Answer 29

for breaking down vasoactive peptides, such as angiotensin I and II, bradykinin, and natriuretic peptides Inhibition of neprilysin augments the activity of the vasoactive peptides. ◼ To maximize the effect of natriuretic peptides, stimulation of the RAAS must be offset without further increase in bradykinin. ◼ Therefore an ARB, instead of an ACE inhibitor, is combined with a neprilysin inhibitor to reduce the incidence of angioedema.

Question 30

Sacubitril/valsartan Q1 :Which one is arb, Which is neprilysin ? Q2 :Inhibition of neprilysin results in Q3 : together, the combination decreases Q4 :ARNI improve what better than ACE ? Therapeutic use :

Answer 30

◼ Sacubitril/valsartan combines the actions of an ARB with neprilysin inhibition. ◼ Inhibition of neprilysin results in increased concentration of vasoactive peptides, leading to natriuresis, diuresis, vasodilation, and inhibition of fibrosis. ◼ Together, the combination decreases afterload, preload, and myocardial fibrosis. ◼ An ARNI improves survival and clinical signs and symptoms of HF,as compared to therapy with an ACE inhibitor. ◼ An ARNI should replace an ACE inhibitor or ARB in patients with HFrEF who remain symptomatic on optimal doses of a β-blocker and an ACE inhibitor or ARB

Question 31

Pharmacokinetics of Sacubitril/valsartan

Answer 31

◼ Sacubitril/valsartan is orally active, administered with or without food, and quickly breaks down into the separate components. ◼ Sacubitril is transformed to active drug by plasma esterases. ◼ Both drugs have a high Vd and are highly bound to plasma proteins. ◼ Sacubitril is mainly excreted in the urine. ◼ The t1/2 of approximately 10 hours for both components allows for twice-daily dosing.

Question 32

Adverse effects of Sacubitril/valsartan

Answer 32

◼ The adverse effect profile is similar to that of an ACE inhibitor or ARB. ◼ Because of the added reduction of afterload, hypotension is more common with an ARNI. ◼ Due to inhibition of neprilysin with sacubitril, bradykinin levels may increase and angioedema may occur. ◼ Therefore, the combination is contraindicated in patients with a history of hereditary angioedema or angioedema associated with an ACE inhibitor or ARB. ◼ To minimize risk of angioedema, an ACE inhibitor must be stopped at least 36 hours prior to starting sacubitril/valsartan.

Question 33

Hyperpolarization-Activated Cyclic Nucleotide–Gated Channel Blocker (HCN) Q1: SA node effect ? Q2:What happen if we inhibit HCN ? Q3:is it Dose Dependent ?

Answer 33

is responsible for the If current and setting the pace within the SA node. Inhibition of the HCN channel results in slowing of depolarization and a lower HR. Yes

Question 34

HCN : Q1: Ivabradine Actions ? Q2: Ivabradine Therapeutic use Q3: Ivabradine Pharmacokinetics Q4: Ivabradine Adverse effects

Answer 34

◼ By selectively slowing the If current in the SA node, reduction of HR occurs without a reduction in contractility, AV conduction, ventricular repolarization, or blood pressure. ◼ In patients with HFrEF, a slower HR increases stroke volume and improves symptoms of HF. ------------------------------------------------ ◼ Ivabradine is utilized in HFrEF to improve symptoms in patients who are in sinus rhythm with a HR above 70 beats per minute and are on optimized HF pharmacotherapy. ◼ Specifically, patients should be on an optimal dose of β-blocker or have a contraindication to β-blockers --------------------------------------------------- ◼ Ivabradine should be administered with meals to increase absorption. ◼ It undergoes extensive first-pass metabolism by CYP3A4 to an active metabolite, which is also a 3A4 substrate. ◼ Ivabradine has a high Vd and is 70% protein bound. ◼ The half-life is 6 hours, which allows for twice-daily dosing. ---------------------------------------------------------------- ◼ **Bradycardia** may occur, which may improve with dose reduction. ◼ Because ivabradine is mostly selective for the SA node, it is not effective for rate control in atrial fibrillation and has been shown to **increase the risk of atrial fibrillation.** ◼ Ivabradine inhibits similar channels in the eye, and luminous phenomena may occur early in therapy. ◼ This enhanced brightness may be ameliorated by dose reduction. ◼ Ivabradine should not be used in pregnancy or breast-feeding, with more advanced heart block, or with potent 3A4 inhibitors

Question 35

Dilation of venous blood vessels leads to

Answer 35

a decrease in cardiac preload by increasing the venous capacitance.

Question 36

commonly used venous dilators

Answer 36

Nitrates , to reduce preload for patients with chronic HF

Question 37

commonly used Arterial dilators

Answer 37

(hydralazine) reduce systemic arteriolar resistance and decrease afterload.

Question 38

Why we would use Vaso- and Venodilators ?

Answer 38

If the patient is intolerant of ACE inhibitors or ARBs, or if additional vasodilator response is required, a combination of hydralazine & isosorbide dinitrate may be used. A fixed-dose combination of these agents has been shown to improve symptoms and survival in black patients with HFrEF on standard HF treatment (β-blocker plus ACE inhibitor or ARB).

Question 39

Vaso- and Venodilators adverse effects (combination of hydralazine & isosorbide dinitrate)

Answer 39

Headache, dizziness, and hypotension Rarely, hydralazine has been associated with drug-induced lupus.

Question 40

INOTROPIC DRUGS Q1: Positive inotropic agents enhance what ? Q2: What the effect of inotropic drugs in HFrEF ?

Answer 40

cardiac contractility and, thus, increase CO. All positive inotropes in HFrEF that increase intracellular Ca concentration have been associated with **reduced survival**. For this reason, these agents, with the exception of digoxin, are only used for a short period mainly in inpatient setting.

Question 41

Digitalis glycosides

Answer 41

◼ They are a group of chemically similar compounds that can increase the contractility of the heart muscle. ◼ The drugs have a low therapeutic index. ◼ The only available agent is digoxin

Question 42

**Digoxin** (Digitalis glycosides) Mechanism of action:

Answer 42

By inhibiting the Na+/K+–ATPase digoxin **reduces** the ability of the myocyte to **actively pump Na+ from the cell**. This ultimately results in a small but physiologically important **increase in free Ca2+**, thereby leading to increased cardiac contractility

Question 42

Actions of digoxin

Answer 42

1) **Increased contractility of the cardiac muscle:** Digoxin increases the force of cardiac contraction, causing the CO to be more closely resemble that of the normal heart. 2) **Vagal tone** is also enhanced, so both heart rate and myocardial oxygen demand decrease 3) **Digoxin slows down conduction velocity through the AV node**, which accounts for its use in *atrial fibrillation.* 3) Neurohormonal inhibition ❑low-dose digoxin inhibits sympathetic activation with minimal effects on contractility. ❑This effect is the reason a lower serum drug concentration is targeted in HFrEF.

Question 42

Therapeutic uses of digoxin

Answer 42

* Digoxin therapy is indicated in patients with HFrEF who are symptomatic on optimal HF pharmacotherapy. * A low serum concentration (0.5 to 0.8 ng/ml) is beneficial in HFrEF

Question 43

Pharmacokinetics of digoxin

Answer 43

* Digoxin is available in oral and injectable formulations. * Digoxin has a large Vd, because it accumulates in muscle. * In acute situations such as symptomatic atrial fibrillation, a loading dose is used. * Digoxin has a long half-life of 30-40 hours. * It is mainly eliminated intact by the kidney, requiring dose adjustment in renal dysfunction.

Question 44

Q1:Adverse effects of digoxin and how we can reduce the side effect ? Q2: is digoxin substrate of p-gp ? what the effect of inhibitor ? Q3: Digoxin with drug such as β-blockers, verapamil, and diltiazem what will happen ?

Answer 44

1-Anorexia, nausea, vomiting, blurred vision, or yellowish vision may be initial indicators of toxicity. 2-When Na+/K+-ATPase resting membrane potential may increase increasing the risk of arrhythmias. 3- hypokalemia With the use of a lower serum drug concentration in HFrEF, toxic levels are infrequent. ------------------------------------------------------- ◼Digoxin is a substrate of P-gp, and inhibitors of P-gp, such as clarithromycin, verapamil, and amiodarone, can significantly increase digoxin levels, necessitating a reduced dose of digoxin. ----------------------------------------------------------- ◼ Digoxin should also be used with caution with other drugs that slow AV conduction, such as β-blockers, verapamil, and diltiazem.

Question 45

β-Adrenergic agonist Q1: β-Adrenergic agonists (dobutamine and dopamine) effect/mechanisim ? Q2: Dosage Form , short term or long ?

Answer 45

improve cardiac performance by causing positive inotropic effects and vasodilation β-Adrenergic agonists ultimately lead to increased entry of calcium ions into myocardial cells and enhanced contraction. --------------------------------------------------------- Both drugs must be given by IV infusion and are primarily used in the short-term treatment of acute HF in a hospital setting.

Question 46

Phosphodiesterase inhibitors Q1 : Milrinone increase what ? Q2 : How Milrinone work , dosage form , short term or long?

Answer 46

the intracellular concentration of cAMP. ---------------------------------------------- ◼Like β-adrenergic agonists, this results in an increase of intracellular calcium and, therefore, cardiac contractility. ◼ Milrinone is usually given by IV infusion for short-term treatment of acute HF. However, dobutamine and milrinone may also be considered for intermediate-term treatment in the outpatient setting for palliative care.

Question 47

In acute decompensated CHF, drugs that reduce preload result in

Answer 47

improvement in HF symptoms such as dyspnea. Most often, IV diuretics are utilized in the acute setting to reduce preload.

Question 48

When IV diuretics are minimally effective

Answer 48

recombinant B-type natriuretic peptide (BNP), or nesiritide , can be used as an **alternative**.

Question 49

About natriuretic peptide (BNP), or nesiritide Q1: Mechanism of action and dosage form ? Q2: Pharmacokinetic ? Q3: Adverse Effect ?

Answer 49

Through binding to natriuretic peptide receptors, nesiritide stimulates natriuresis and diuresis and reduces preload and afterload Nesiritide is administered IV as a bolus (most often) and continuous infusion. ------------------------------------------------------------ Like endogenous BNP, nesiritide has a short half-life of 20 minutes and is cleared by renal filtration, cleavage by endopeptidases and through internalization after binding to natriuretic peptide receptors --------------------------------------------------------------- The most common adverse effects are hypotension and dizziness, and like diuretics, nesiritide can worsen renal function

Question 50

Order of Therapy

Answer 50

Guidelines have classified HF into *four stages*, from least to most severe. ◼ Note that as the disease progresses, **polytherapy** is initiated. ◼1- In patients with overt HF, loop diuretics are often introduced first for relief of signs or symptoms of volume overload, such as dyspnea and peripheral edema. ◼ 2- ACE inhibitors or ARBs are added after the optimization of diuretic therapy. ◼ The dosage is gradually titrated to that which is maximally tolerated and/or produces optimal cardiac output. ◼ 3- Historically, β-blockers were added after optimization of ACE inhibitor or ARB therapy; ◼ however, most patients newly diagnosed with HFrEF are initiated on both low doses of an ACE inhibitor and β-blocker after initial stabilization. ◼ These agents are slowly titrated to optimal levels to increase tolerability. ◼4- Aldosterone antagonists and fixed-dose hydralazine and isosorbide dinitrate are initiated in patients who continue to have HF symptoms despite optimal doses of an ACE inhibitor and β-blocker. ◼ Once at an optimal ACE inhibitor or ARB dose and if the patient remains symptomatic, either can be replaced by sacubitril/valsartan. ◼ 5- Lastly, digoxin and ivabradine are added for symptomatic benefit only in patients on optimal HF pharmacotherapy