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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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 Heart Failure

- Higher doses ↑ cardiac force & BP - PK: Oral

- PK: Given IV, short duration - Use: Chronic HF
- Use: Acute decompensated heart failure, Angiotensin - Same actions as ACEI, but less efficacious
shock Receptor - Candesartan + ACEI = beneficial
- Toxicity:Arrhythmias, tachycardia, ↑ risk of Blockers - Use: For patients intolerant of ACE
angina (due to ↑ O2 consumption via beta-
(-sartan) inhibitors because of incessant cough
stimulation), tachyphylaxis, Additive effect
- PK: Oral
with other sympathomimetics
Aliskiren - Renin inhibitor
Epinephrine - Direct agents
- Similar effects with that of ACEI
- NE: “Last-resort” to ↑ BP in shock due to its
- Approved for HPN and heart failure
non-affinity to β2 receptors (no
Norepinephrine vasodilation)
3. VASODILATORS
- β-selective agonist  Effective in acute heart failure because they provide ↓preload
Isoproterenol
- ↑ HR & ↑ Contractility (venodilation) or ↓afterload (arteriolar dilation) or both

Dopamine and Dobutamine are indirect agents. They need to recruit

Selected Vasodilators used in Heart Failure
epinephrine and norepinephrine to eilicit the increase in HR & contractility
Drug MOA
Drugs Without Inotropic Effects
- MOA:Venodilator; releases NO &
 The first-line therapies for chronic heart failure. activates guanylylcyclase
1. DIURETICS - ↓ preload and ventricular stretch
 MOA in HF: ↓ Venous pressure and ventricular preload ↓ salt and IsosorbideDinitrate - PK: Oral; duration 4-6 h
water retention; no direct effect on cardiac contractility - Use: Acute & chronic HF
 Diuretics (especially furosemide) are drugs of choice in heart - Toxicity: Postural hypotension,
failure tachycardia, headache
 Mainstay of heart failure management
- MOA:Arteriolar dilator; increases
Selected Diuretics used in Heart Failure NO synthesis in endothelium
- ↓ afterload  ↑ CO
Drug MOA Hydralazine
- PK: Oral; duration 8-12 h
- MOA:↓ NaCl&KCl reabsorption in thick - Toxicity: Tachycardia, fluid
ascending limb of loop of Henle retention, SLE-like syndrome
- ↑ NaCl& H2O Excretion
- MOA:Arteriolar&venodilator;
- ↓ preload& afterload
spontaneously releases NO &
- ↓ pulmonary & peripheral edema
Furosemide activates guanylylcyclase
- PK:Oral, IV; Duration: 2-4h
Nitroprusside - ↓ afterload, ↓ preload
- Use: Acute & chronic HF
- Use: Acute decompensated failure
- Toxicity: Hypovolemia, hypokalemia,
- PK: IV only; duration 1-2 min
orthostatic hypotension, ototoxicity,
- Toxicity: Excessive hypotension,
sulphonamide allergy
cyanide toxicity
- MOA: ↓ NaCl reabsorption in DCT - MOA: Synthetic form of brain
- Same effects as furosemide but less natriuretic peptide, activates BNP
efficacious receptors
- PK:Oral; Duration: 10-12 h - ↑ cGMP in smooth muscles
HCTZ
- Use: Mild chronic HF - ↓ venous and arteriolar tone
- Toxicity:Hyponatremia, hypokalemia, Nesiritide - Diuresis
hyperglycemia, hyperuricemia, Carperitide - Use: Acute decompensated failure;
hyperlipidemia, sulphonamide allergy Ularitide useful as diagnostic and
- MOA: Blocks aldosterone receptors in prognostic test
collecting tubules - PK: IV only; duration 18 min
- ↑ NaCl& H2O Excretion - Administered as bolus IV
Spironolactone, - ↓ Remodeling, ↓ mortality - Toxicity: Excessive hypotension,
Eplerenone - PK: Oral; Duration: 24-72 h renal damage
- Use:Chronic HF - Active competitive inhibitors of
- Toxicity:Hyperkalemia, gynecomastia (for endothelin
spironolactone) Bosentan - Shown benefits in experimental
animal models with heart failure
Tezosentan - In human trials: teratogenic and
2. AGENTS ACTING ON RAAS
hepatotoxic effects but useful in
Drug MOA pulmonary HPN
- ↓ Peripheral resistance  ↓ afterload
- ↓ Aldosterone secretion  ↓ salt and water 3. BETA BLOCKERS
ACE Inhibitors retention  ↓ preload This drug group can precipitate acute decompensation of cardiac
(-pril) - ↓ angiotensin levels on tissue  ↓ function
sympathetic activity 1. Metoprolol, Bisoprolol, Carvedilol, Nebivolol
- ↓ long-term remodeling of the heart and o Reduction in mortality in patients with stable severe heart
vessels ↓ mortality and morbidity failure
- Begin at low doses and titrate as needed o Suggested mechanisms

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 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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