Download CVS 3 [Recovered]

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Cardiac failure
Heart failure (HF) is a
complex, progressive
disorder in which the heart
is unable to pump sufficient
blood to meet the needs of
the body.
Its cardinal
symptoms are dyspnea,
fatigue, and fluid
retention.
OVERVIEW
HF is due to an impaired ability of the heart to
adequately fill with and/or eject blood.
 It is often accompanied by abnormal increases in
blood volume and interstitial fluid

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OVERVIEW

Underlying causes of HF include arteriosclerotic
heart disease, myocardial infarction,
hypertensive heart disease, valvular heart
disease, dilated cardiomyopathy, and congenital
heart disease.
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COMPENSATORY MECHANISMS
 SYMPATHETIC
ACTIVITY INCREASES
 BETA RECEPTORS STIMULATED
 HR INCREASES
 FORCE OF CONTRACTION
INCREASES
ALPHA RECEPTORS
STIMULATED
 VENOUS RETURN INCREASES
 PRE LOAD INCREASES

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CONSEQUENCES OF HEART FAILURE
CO DECREASES
 RBF DECREASES
 INCREASES ANGIOTENSIN II
 INCREASES ALDOSTERONE

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CONSEQUENCES OF HEART FAILURE
PERIPHERAL RESISTANCE INCREASES
 SODIUM AND WATER RETENTION
 BLOOD VOLUME INCREASES
 MAY RESULT

PERIPHERAL EDEMA
 PULMONARY EDEMA

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COMPENSATORY PHYSIOLOGICAL
RESPONSES IN HF
1. Increased sympathetic activity:
 2. Activation of the renin–angiotensin
aldosterone system:
 3. Myocardial hypertrophy:

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ACUTE (DECOMPENSATED) HF
If the adaptive mechanisms adequately restore
cardiac output, HF is said to be compensated.
 If the adaptive mechanisms fail to maintain
cardiac output, HF is decompensated and the
patient develops worsening HF signs and
symptoms.
 Typical HF signs and symptoms include dyspnea
on exertion, orthopnea, paroxysmal
nocturnal dyspnea, fatigue, and peripheral
edema.

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CHEST X-RAY- CHF

Note the enlarge
Heart (greater than ½
chest diameter on a
PA film)
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CONGESTIVE HEART FAILURE
(CHF)
The treatment of CHF aims to reduce preload
and afterload and to increase myocardial
contractility mainly by administration of:
1) angiotensin-converting enzyme
inhibitors,
2) angiotensin-receptor blockers, 3)
aldosterone antagonists, 4) β-blockers, 5)
diuretics, 6) direct vaso- and venodilators,
and 7) inotropic agents
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THERAPEUTIC STRATEGIES IN HF
Chronic HF is typically managed by fluid
limitations (less than 1.5 to 2 L daily);
 REDUCE PHYSICAL ACTIVITY
 DECREASE SODIUM IN DIET
 VASODILATORS
 DIURETICS
 IONOTROPICS
 Note: Inotropic agents are reserved for acute HF
signs and symptoms in mostly the inpatient setting.
 Drugs that may precipitate or exacerbate HF, such
as nonsteroidal anti-inflammatory drugs (NSAIDs),
alcohol, nondihydropyridine calcium channel
blockers, and some antiarrhythmic drugs, should 15be
avoided if possible.


4 classes of drugs effective in reducing the
symptoms and prolong life
 1.
ACEIs– reduce afterload and preload
 2. Diuretics – decrease extracellular fluid
volume
 3. ARBs – decrease preload and afterload
 4. Beta blockers.
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1. АСЕ inhibitors
Angiotensin
Renin
Angiotensin I
()
receptor
AT2-
receptor
Kinins
Angiotensin II
AT1-
ACE
inhibitors
ACE
(kininase II)
Breakdown
ACE
()
ACE INHIBITORS
reduce pre- and afterload.
 They are administered in lower
doses alone or together with diuretics,
cardiac glycoside, anti-ischemic agents,
etc. in all stages of CHF, due to systolic
dysfunction.
Adverse effects:
 These include postural
hypotension, renal insufficiency,
hyperkalemia, a persistent dry
cough, and angioedema (rare).

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ANGIOTENSIN
RECEPTOR BLOCKER
Angiotensin II receptor blockers (ARBs) are
medications that block the action of angiotensin
II by preventing angiotensin II from binding to
angiotensin II receptors on the muscles
surrounding blood vessels.
 As a result, blood vessels enlarge (dilate) and
blood pressure is reduced. Reduced blood
pressure makes it easier for the heart to pump
blood and can improve heart failure.

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In addition, the progression of kidney
disease caused by the high blood pressure or
diabetes is slowed.
 ARBs have effects that are similar to angiotensin
converting enzyme (ACE) inhibitors, but ACE
inhibitors act by preventing the formation of
angiotensin II rather than by blocking the
binding of angiotensin II to muscles on blood
vessels.
 ARBs do not affect bradykinin levels

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ALDOSTERONE ANTAGONISTS
Patients with advanced heart disease have elevated
levels of aldosterone due to angiotensin II stimulation
and reduced hepatic clearance of the hormone.
 Spironolactone [spy-ro-no-LAC-tone] is a direct antagonist
of aldosterone, thereby preventing salt retention,
myocardial hypertrophy, and hypokalemia.
 Eplerenone [eh-PLEH-reh-none] is a competitive
antagonist of aldosterone at mineralocorticoid receptors.

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IONOTROPIC AGENTS
 GLYCOSIDE


DIGOXIN
DIGITOXIN
 BETA


AGONIST
DOPAMINE
DOBUTAMINE
 PHOSPHO


DIESTERASE INHIBITORS
AMRINONE
MILRINONE
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BETA AND ALPHA BLOCKING AGENTS
 Carvedilol
is a blocker of β- and α receptors.
It
also
has
antioxidant,
vasodilating and cardioprotective effects. It
decreases
cardiac
output,
peripheral
vascular
resistance
and
afterload.
Carvedilol lowers mortality with 25–67%.
 The treatment begins with low doses (3.125
mg/12 h).
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Beta-blocking agents
Cardioselective beta-blockers Bisoprolol and
Metoprolol decrease with 31% mortality in
patients with CHF, if used in combination with
diuretics, ACE inhibitors and Digoxin.
THIAZIDES AND LOOP DIURETICS
They increase salt and water loss,
reduce blood volume and lower
excessive venous filling pressure,
reduce circulating blood volume and
preload.
 The congestive features of oedema, in
the lungs and periphery, are alleviated,
cardiac output is also increased.


Diuretics are administered together
with ACE inhibitors and other drugs.
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VASO- AND VENODILATORS
Dilation of venous blood vessels leads to a decrease in
cardiac preload by increasing venous capacitance.
 Nitrates are commonly used venous dilators to
reduce preload for patients with chronic HF.
 Arterial dilators, such as hydralazine [hye-DRALa-zeen] reduce systemic arteriolar resistance
and decrease afterload.
 If the patient is intolerant of ACE inhibitors or βblockers, or if additional vasodilator response is
required, a combination of hydralazine and
isosorbide dinitrate [eye-soe-SOR-bide dye-NYEtrate] may be used. hydralazine has been associated
with drug-induced lupus.

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VASODILATORS
Vasodilator therapy with nitroprusside or
nitroglycerin is often used for acute severe failure
with congestion.
 Reduction in cardiac size and improved efficiency
that can be realized with proper adjustment of
venous return (preload) and reduction of
resistance to ventricular ejection ( afterload)

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VASODILATORS
The natriuretic peptide nesiritide acts chiefly by
causing vasodilation.
 Binds to natriuretic peptide receptors, thus
increase cGMP, resulting in vasodilation.
 Used in acute decompensated CHF

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Cardiac glycosides (CGs)
France, UK
Nativelle
(1869)
•Digitoxin
Digitalis purpurea (Foxglove)
W. Withering (1785)
MECHANISM

Direct inhibition of Na+/K+ ATPase

↓ Na+ gradient results in indirect inhibition of
Na+/Ca2+ exchanger/antiport
↑ [Ca2+]i → positive inotropy
 Vagal stimulation


results in increased cardiac output via
decreased heart rate
 increased filling time

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CARDIAC GLYCOSIDES
MECHANISM
 INHIBIT
SODIUM POTASSIUM PUMP
 INTRACELLULAR
 CALCIUM
EXCHANGE DECREASE
 CYTOPLASM
 FORCE
SODIUM INCREASES
Ca++ INCREASES
OF CONTRACTION INCREASES
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Ex
3Na+
Na+/K+
ATP-ase
(–)
2K+
3Na+
Na+/Ca2+
exchange
Ca2+
In
DIGOXIN
PHARMACOKINETICS
 DIGOXIN
 ORAL
AND IV
 LARGE VOL OF DISTRIBUTION


has a long half-life of 30 to 40 hours.
It is mainly eliminated intact by the kidney, requiring
dose adjustment in renal dysfunction.
 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.
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SIDE EFFECTS
Blurry yellow vision(xanthopsia),
 Nausea, vomiting, diarrhea



cholinergic effects
Life-threatening arrhythmias

↑ PR, ↓ QT, T-wave inversion
Hyperkalemia
 Renal insufficiency causes ↑ digoxin toxicity
 Hypokalemia causes ↑ digoxin toxicity



without K+, digoxin can bind to Na+/K+ ATPase
digoxin competes for excretion and competes for tissuebinding sites
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ANTIDOTE
Slowly normalize K+
 Give lidocaine
 Give digoxin antibodies (anti-dig Fab fragments)
 Give Mg2+

Also remember:
 Digoxin should also be used with caution with
other drugs that slow AV conduction, such as βblockers, verapamil, and diltiazem.

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Β-ADRENERGIC AGONISTS
 DOPAMINE
 DOBUTAMINE
Mostly slow IV route.
 β-Adrenergic agonists, such as dobutamine [doeBYOO-ta-meen] and dopamine [DOH-puh-meen],
improve cardiac performance by causing positive
inotropic effects and vasodilation.
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Β-ADRENERGIC AGONISTS
Dobutamine is the most commonly used
inotropic agent other than digoxin.
 β-Adrenergic agonists lead to an increase in
intracellular cyclic adenosine monophosphate
(cAMP), which results in the activation of protein
kinase.
 Protein kinase then phosphorylates slow calcium
channels, thereby increasing entry of calcium
ions into the myocardial cells and enhancing
contraction

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PHOSPHODIESTERASE
INHIBITORS
AMRINONE
MILRINONE
 Mech: cAMP INCREASES
 CYTOPLASM CALCIUM LEVELS ↑
 Increase cardiac contractility
 SE: THROMBOCYTOPENIA
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Alternative methods for treatment of severe
CHF
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