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Dec 11, 2017
Therapeutics – Gastrointestinal Tract
HEART FAILURE

o Does not respond optimally with positive inotropic drugs

Outline
I. Case
Pathophysiology of Heart Failure
a. Therapeutic Objectives
b. Introduction  Low-output failure: reduced cardiac output
c. Diagnosis  High-output failure: the demands of the body exceeds the normal
d. Pharmacotherapeutics cardiac output e.g.,
e. Outcomes o hyperthyroidism
II. Appendices o beriberi
a.) Sample Prescription o anemia
b.) Quiz of Section 3B o arteriovenous shunts
 Compensatory Mechanisms of the Heart:
References: Myocardial hypertrophy
CTC – Heart Failure Case o Most important intrinsic compensatory mechanism
Katzung o The increase in muscle mass helps maintain cardiac
Harrisons 18th ed performance
Pharma Trans 2017 – Heart Failure Remodelling
o Dilation and other slow, chronic structural changes that
happen to a stressed myocardium during heart failure
o May include proliferation of connective tissue cells as well as
CASE 9
abnormal myocardial cells with some biochemical
55/M A.D. was brought to the E.R. because of shortness of breath. He was characteristics of fetalmyocytes. (*moving on, letting go –
previously diagnosed with Chronic Heart Failure. Patient had verbalized mabagalperosigurado)
that he had difficulty lying down flat on bed and noticed peripheral o Ultimately, myocytes in the failing heart die at an accelerated
edema. He is currently on DPP4 – Linagliptin 5 mg because he had rate through apoptosis, leaving the remaining myocytes
elevated creatinine before. He also took Digoxin recently but decided to subject to even greater stress.
stop. He was taking Enalapril but this caused him frequent cough so he Redistribution of Blood Flow
also decided to stop. His regular blood pressure was 160/100. What will Blood flow to the periphery is reduced  blood flow is shunted
you give this patient? to vital organs like the Brain, Kidney, Liver and Lungs
Therapeutic Objectives
1. Relieve or reduce symptoms
2. Improve the patient’s quality of life
3. Prevent future readmissions for exacerbations
4. Prolong patient’s survival

Introduction
 Heart failure is a chronic progressive condition that affects the
heart’s ability to properly pump blood.
 It refers to the stage in which fluid builds up around the heart and
causes it to pump inefficiently. It usually develops when the
ventricles are unable to pump sufficient blood to be delivered to
the body.
 HF occurs when cardiac output (CO) is not enough to meet the
oxygen demands of the body
 CO = HR x SV
 SV= EDV-ESV
 5-year mortality rate is 50%
 Most common cause is Coronary Artery Disease (CAD)
 Progressive disease characterized by gradually decreasing CO
punctuated by intermittent acute decompensations
 Treatment goals:
o Reducing the symptoms and slowing progression
o Managing episodes of decompensation

Types of Heart Failure

 Ejection Fraction (EF) – fraction of outbound blood pumped with
each heartbeat: SV/EDV
1. Systolic Heart Failure
o Represents 50% of patients with decreased contractility
resulting in decreased EF; reduced contractility & ejection Chronic heart failure is associated with increased venous capacitance and
fraction lymphatic drainage of the lung. As a result, crackles are often absent, even
o Typical of acute failure, especially that resulting from in the setting of elevated pulmonary capillary pressure. Continued sodium
myocardial infarction retention preferentially results in peripheral edema and, ultimately, in the
2. Diastolic Heart Failure development of pleural effusions. With acute decompensation, the
o Stiffening and loss of adequate relaxation resulting in pulmonary capillary membrane may succumb to increased pressure, with
reduced filling pressures and cardiac output (SV is reduced shearing of the capillary and release of fluid, protein, and occasionally red
but EF may be normal/preserved) blood cells into the alveoli. The lungs’ response will include cough, to expel

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 Heart Failure

the fluid in the alveoli. The long-term response to elevated pulmonary Clinical Criteria for the Diagnosis of CHF
venous pressure includes interstitial fibrosis with thickening of the alveolar Framingham Criteria
membrane. Thus, severe, chronic heart failure can result in interstitial
fibrosis and a restrictive lung disease.

New York Functional Classification of Heart Failure

Table 1. NYFC of Heart Failure

ACC/AHA STAGES

 Oldest, studied longest, and followed most extensively

 (+) if 2 major + 2 minor criteria are present
 Have very low specificity

Boston Criteria

 Stages in the development if heart failure:

o Stage A – patients are in high risk because of other disease
but have no signs or symptoms of heart failure
o Stage B – evidence of structural heart disease but no
symptoms of heart failure
o Stage C – patients have structural heart disease and
symptoms of failure, and symptoms are responsive to
ordinary therapy. Severity of heart failure is describe when
this stage is reached
o Stage D – patients have heart failure refractory to ordinary
therapy, and special interventions (resynchronization
therapy, transplant) are required

 Uses 3 clinical parameters in the diagnosis of CHF: History, PE and

Chest Radiography Results
 Most sensitive and specific

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 Heart Failure

LSDHF vs RSDHF - Cardiac glycosides affect all excitable tissues (eg, smooth
muscle and CNS)
- Heart:Arrhythmia (tachycardia which proceeds to fibrillation)
due to development of delayed after-depolarizations that
eventually couples with the normal ECG

Fig 5.Contraction of normal heart (top), Heart w/ digoxin in

*Imaging modalities will not anymore be discussed- Please refer to Med
therapeutic dose (middle), and at toxic dose (bottom). Arrow
Trans of Heart Failure for the elaborative discussion of the Imaging
shows the premature depolarization in digoxin toxicity
Modalities used in HF.

Pharmacotherapeutics - GI (2nd most common site of toxicity): Anorexia, nausea,

Positive Inotropic Drugs vomiting, diarrhea
- CNS (less often): Disorientation, hallucinations, visual
*Lifted from Pharma Trans 2017 of Heart Failure
disturbances
1. Cardiac Glycosides (Cardenolides) - Hypokalemia&hypercalcemia exacerbates digitalis toxicity
Digoxin(Lanoxin™) Indications
Chemistry - Heart failure & atrial fibrillation
- Prototype cardenolide - Usually given when diuretics and ACE inhibitors have failed
- Sugar group + Steroid nucleus + lactone ring - Clinical monitoring of plasma digoxin is warranted to prevent
toxicity
Contraindications
- Wolff-Parkinson White syndrome
- Atrial fibrillation (angguloniKatzung, sabi indicated daw sa
atrial fibrillation perongayon CI naman?)

2. BIPYRIDINES
1. Milrinone
o MOA: Inhibits phosphodiesteraseisozyme 3 (PDE-3)
o PDE-3inhibition - ↑cAMP↑ Contractility due to ↑ inward
Ca2+ flux ; ↑cAMP hasvasodilatory effect
o PK:
 Given IV
 t½ = 3-6 hrs
Pharmacokinetics  10-40% elimination via the kidney
- Dose: Oral (BA 65%-80%), IV o Toxicity: arrhythmias
- Well-distributed o Inamrinone – discontinued
- CNS entry
- t½ = 36-40 hrs 3. BETA AGONISTS
- Narrow therapeutic index Drug MOA
Pharmacodynamics - β1- Selective agonist (↑ cAMP)
- MOA: Inhibits Na+/K+-ATPase pump (Refer to Fig 1) - ↓ exit of - ↑ Contractility  ↑ CO
Na in cardiac myocyte ↓ NCX activity  ↑ cytoplasmic - ↓ ventricular filling pressure
Ca2=with ↑ sequestration by SERCA - PK: Given IV, short duration
- Cardiac Mechanical Effects: - Use:Chronic heart failure (via intermittent
- ↑Contraction (due to ↑Ca2+ in the contractile proteins Dobutamine infusion), acute decompensated heart
during systole) failure
- Cardiac Electrical Effects(mostly by PANS vagal stimulation): - Toxicity: Arrhythmias, tachycardia, ↑ risk of
- Sinus Node: ↓ Rate angina (due to ↑ O2 consumption via beta-
- Atrial Muscle: ↓ Refractory Period stimulation), tachyphylaxis, Additive effect
- AV Node: ↓ Conduction velocity with other sympathomimetics
- Purkinje system & ventricles: Slight ↓ refractory period - Dopamine receptor agonist; higher doses
- ECG: ↑PR interval, ↓QT interval Dopamine activate β& α receptors
Toxicity - ↑ renal blood flow

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- Higher doses ↑ cardiac force & BP
- PK: Given IV, short duration
- Use: Acute decompensated heart failure,
shock
- Toxicity:Arrhythmias, tachycardia, ↑ risk of
angina (due to ↑ O2 consumption via beta-
stimulation), tachyphylaxis, Additive effect
with other sympathomimetics
Epinephrine - Direct agents
- NE: “Last-resort” to ↑ BP in shock due to its
non-affinity to β2 receptors (no
Norepinephrine vasodilation)
- β-selective agonist
Isoproterenol
- ↑ HR & ↑ Contractility
Dopamine and Dobutamine are indirect agents. They need to recruit
epinephrine and norepinephrine to eilicit the increase in HR & contractility
Drugs Without Inotropic Effects
 The first-line therapies for chronic heart failure.
1. DIURETICS
 MOA in HF: ↓ Venous pressure and ventricular preload ↓ salt and
water retention; no direct effect on cardiac contractility
 Diuretics (especially furosemide) are drugs of choice in heart
failure
 Mainstay of heart failure management
Selected Diuretics used in Heart Failure
Drug MOA
- MOA:↓ NaCl&KCl reabsorption in thick
ascending limb of loop of Henle
- ↑ NaCl& H2O Excretion
- ↓ preload& afterload
- ↓ pulmonary & peripheral edema
Furosemide
- PK:Oral, IV; Duration: 2-4h
- Use: Acute & chronic HF
- Toxicity: Hypovolemia, hypokalemia,
orthostatic hypotension, ototoxicity,
sulphonamide allergy
- MOA: ↓ NaCl reabsorption in DCT
- Same effects as furosemide but less
efficacious
- PK:Oral; Duration: 10-12 h
HCTZ
- Use: Mild chronic HF
- Toxicity:Hyponatremia, hypokalemia,
hyperglycemia, hyperuricemia,
hyperlipidemia, sulphonamide allergy
- MOA: Blocks aldosterone receptors in
collecting tubules
- ↑ NaCl& H2O Excretion
Spironolactone, - ↓ Remodeling, ↓ mortality
Eplerenone - PK: Oral; Duration: 24-72 h
- Use:Chronic HF
- Toxicity:Hyperkalemia, gynecomastia (for
spironolactone)
2. AGENTS ACTING ON RAAS
Drug MOA
- ↓ Peripheral resistance  ↓ afterload
- ↓ Aldosterone secretion  ↓ salt and water
ACE Inhibitors retention  ↓ preload
(-pril) - ↓ angiotensin levels on tissue  ↓
sympathetic activity
- ↓ long-term remodeling of the heart and
vessels ↓ mortality and morbidity
- Begin at low doses and titrate as needed
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Heart Failure
- PK: Oral
- Use: Chronic HF
Angiotensin - Same actions as ACEI, but less efficacious
Receptor - Candesartan + ACEI = beneficial
Blockers - Use: For patients intolerant of ACE
(-sartan) inhibitors because of incessant cough
- PK: Oral
Aliskiren - Renin inhibitor
- Similar effects with that of ACEI
- Approved for HPN and heart failure
3. VASODILATORS
 Effective in acute heart failure because they provide ↓preload
(venodilation) or ↓afterload (arteriolar dilation) or both
Selected Vasodilators used in Heart Failure
Drug MOA
- MOA:Venodilator; releases NO &
activates guanylylcyclase
- ↓ preload and ventricular stretch
IsosorbideDinitrate - PK: Oral; duration 4-6 h
- Use: Acute & chronic HF
- Toxicity: Postural hypotension,
tachycardia, headache
- MOA:Arteriolar dilator; increases
NO synthesis in endothelium
- ↓ afterload  ↑ CO
Hydralazine
- PK: Oral; duration 8-12 h
- Toxicity: Tachycardia, fluid
retention, SLE-like syndrome
- MOA:Arteriolar&venodilator;
spontaneously releases NO &
activates guanylylcyclase
Nitroprusside - ↓ afterload, ↓ preload
- Use: Acute decompensated failure
- PK: IV only; duration 1-2 min
- Toxicity: Excessive hypotension,
cyanide toxicity
- MOA: Synthetic form of brain
natriuretic peptide, activates BNP
receptors
- ↑ cGMP in smooth muscles
- ↓ venous and arteriolar tone
Nesiritide - Diuresis
Carperitide - Use: Acute decompensated failure;
Ularitide useful as diagnostic and
prognostic test
- PK: IV only; duration 18 min
- Administered as bolus IV
- Toxicity: Excessive hypotension,
renal damage
- Active competitive inhibitors of
endothelin
Bosentan - Shown benefits in experimental
animal models with heart failure
Tezosentan - In human trials: teratogenic and
hepatotoxic effects but useful in
pulmonary HPN
3. BETA BLOCKERS
This drug group can precipitate acute decompensation of cardiac
function
1. Metoprolol, Bisoprolol, Carvedilol, Nebivolol
o Reduction in mortality in patients with stable severe heart
failure
o Suggested mechanisms
 Heart Failure

 Attenuation of the adverse effects of high

concentrations of catecholamines (including
apoptosis)
 Up-regulation of Beta Receptors
 ↓ HR
 ↓ remodeling through inhibition of the mitogenic
activity of cathecolamines

Clinical Pharmacology
Table 5. Classification & Treatment of Chronic HF
ACC/AHA NYHA
Description Management
Stage1 Class2
Treat obesity, HPN,
No symptoms but
A Prefailure diabetes,
risk factors present
hyperlipidemia, etc
Symptoms with ACEI/ARB, β-
B I
severe exercise blocker, diuretic
Symptoms with Add aldosterone
marked (class II) or antagonist, digoxin;
C II/III
mild (class III) CRT ,
exercise hydralazine/nitrate
Severe symptoms
D IV Transplant, LVAD
at rest
* Please refer to Med Thera Prescription Trans (Drugs For Heart Failure)
for the complete samples of drug prescriptions
DRUG PRESCRIPTION FOR THE CASE

QUIZ

Case: Patient 47 y/o, unknown hypertensive, non-obese. Clinical BP

measurement is 140/90 mmHg. Upon monitoring at home, blood
pressure appears to be normal. Second BP measurement in the clinic is
still above normal levels. RDU?

Drug of Choice: Beta Blocker (Metoprolol)

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