1. Drugs used in treatment of Heart failure II
Dr. Asmaa Fady
PhD., MSC., M.B, B.Ch
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7/24/2019

2. Learning objectives: At the end of this lecture the student should:
List pharmacological classes (&medications) used for compensated heart failure
List pharmacological classes (&medications) used for decompensated (acute) heart failure
Describe the role of each pharmacological class on the compensated mechanisms of heart failure
Explain the mechanism of actions (& therapeutic actions) of each pharmacological class used for heart failure
Identify the adverse effects (with its mechanism), important pharmacokinetic & monitoring parameters, & contraindications
List therapeutic uses of each pharmacological class used for heart failure
اسم ورقم المقرر – Course Name and No.
7/24/2019

3. Pathophysiology of heart failure
Heart failure Definition: inability of the heart to pump sufficient amounts of blood to satisfy the metabolic needs of the body.
Patients usually presented by Dyspnea, fatigue & palpitation.
O2 need
COP
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7/24/2019

4. Classification of heart failure
Based on the severity (body compensation):
1. Compensated (Chronic) heart failure [CHF]
2. Decompensated (Acute) heart failure [AHF]= emergency condition
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5. = SV * HR
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6. Generalized VC
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7. Treatment outlines Problems Solution Low contractility (low COP)
VC (arteries, veins)
Edema & hypervolemia
Remodeling (B1, AT1, aldosterone)
+ inotropic drugs
VD (arterial & venous dilators)
Diuretics & aldosterone antagonists
Cardio protective drugs (BB- ACEI, ARBs, aldosterone antagonists)
Problems
Solution
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8. Drug therapy for heart failure
+ve inotropes
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9. Medications for Compensated HF
1- +ve inotropes: Digoxin 2- Cardio protective drugs: (ACEI, ARBs, BB, aldosterone antagonists) 3- Vasodilators: (D-dil.) 4- Diuretics: loop diuretics.
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7/24/2019

10. What if the body failed to compensate: resulted in acute (decompensated) HF
Body unable to restore C.O that lead to acute hypoperfusion & accumulation of fluids (edema)
How do the pharmacological interventions play role in decompensated (acute) HF?
1- +ve inotropes:
*β- agonist (dobutamine)
*Phosphodiesterase inhibitors (milrinone)
2- Vasodialtors: to overcome (hypoperfusion).
3- Diuretics: Remove excess fluids (edema): Loop diuretics
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11. 2. Cardio protective drugs
a. Angiotensin converting enzyme inhibitors (ACEI).
b. Angiotensin II Receptor Antagonists (ARBs).
c. Beta Blockers.
d. Aldosterone Antagonists
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12. Renin Angiotensin Aldosteron System (RAAS) Antagonists
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13. Angiotensin converting enzyme inhibitors (ACEI): Captopril, Enalapril, Fosinopril, Lisinopril
Mechanism of action:
Inhibit ACE that cleaves angiotensin I to angiotensin II:
*decrease VC.
*decrease Aldosterone.
*inhibit Sympathetic.
*decrease Hypertrophy & Remodeling of heart & BV.
Diminish the inactivation of bradykinin (potent vasodilator) ↑ level of bradykinin: VD.
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14. Angiotensin converting enzyme inhibitors (ACEI): Captopril, Enalapril, Fosinopril, Lisinopril
Actions:
On heart : ↓ ↓ vascular resistance (afterload) > ↓ venous tone (preload) by ↓ angiotensin II, ↓sympathetic activation, & ↑ bradykinin & ↑ C.O.P
* For treatment of HF
On blood vessels: ↓vascular resistance (afterload) by ↓ angiotensin II, ↓sympathetic activation, & ↑ bradykinin & ↓ BP
* For treatment of BP
inhibiting aldosterone release: decrease edema by ↓ Na/H2O retention
*** For both HF & BP (↓ edema & blood volume).
Indications:
HF: * For all stages of chronic heart failure.
Hypertension
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7/24/2019

15. Angiotensin converting enzyme inhibitors (ACEI): Captopril, Enalapril, Fosinopril, Lisinopril
Pharmacokinetics/dosage form:
Given orally usually once daily
Adverse effects:
Hypotension (in hypovolemic state)
Dry cough (Thought to be due to ↑ bradykinin level)
Angioedema (rare): thought to be due to ↑ bradykinin level
Hyperkalemia: Potassium levels must be monitored
Skin rash (allergy)
Contraindications:
Pregnancy (teratogenic agents may induce fetal malformations).
Renal impairment.
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16. Angiotensin II Receptor Antagonists (ARBs): Candesartan, Losartan, Telmisartan, Valsartan
ARBs are substitute for ACE inhibitors in those patients who cannot tolerate ACE inhibitors.
M.O.A:
Block the angiotensin II type 1 (AT1) receptors, decreasing the activation of AT1 receptors by angiotensin II.
UNLIKE ACE inhibitors, ARBs DON’T ↑ level of bradykinin
Actions:
Similar to ACE inhibitors (unless ARBs don’t ↑ level of bradykinin)
Indications:
HF Especially for patients who can’t tolerate ACE inhibitors because of dry cough or angiodema secondary to ↑ level of bradykinin
Hypertension
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7/24/2019

17. Angiotensin II Receptor Antagonists (ARBs): Candesartan, Losartan, Telmisartan, Valsartan
Pharmacokinetics/dosage form:
Given orally usually once daily
Monitoring Parameters:
Serum creatinine & K+ level
Adverse effects:
o Similar to ACE inhibitors
o BUT lower incidence of dry cough & angioedema (why?)
Contraindications:
Pregnancy (teratogenic agents may induce fetal malformations).
Renal impairments
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7/24/2019

18. β-blockers (BBs) β-blockers have shown benefit (↓ mortality) in HF:
M.O.A & Action:
↓ chronic activation of the sympathetic nervous system by ↓ HR, contractility, & inhibiting the release of renin in the kidneys ,↓ heart workload, ↓ cardiac remodeling, hypertrophy, and cell death
β-blockers have shown benefit (↓ mortality) in HF:
Carvedilol (nonselective BB with α1-adreno-receptors antagonist, has additive antioxidant effect)
Bisoprolol (β1-selective antagonist)
Long-acting metoprolol succinate (β1-selective antagonist)
Avoid Beta blockers During Decompensated (Acute) HF.
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7/24/2019

19. Aldosterone Antagonists: Spironolactone and Eplerenone
M.O.A & Actions: o Act as antagonist of aldosterone at its receptor sites inhibit Na/H2O retention ↑ Na/H2O excretion while ↑ K+ retention ↓ fluid accumulation (↓ edema & ultimately may ↓ myocardial hypertrophy) & ↑K+ level (Hyperkalemia) o Spironolactone is a direct antagonist of aldosterone o Eplerenone is a competitive antagonist of aldosterone at mineralocorticoid receptors.
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20. Aldosterone Antagonists: Spironolactone and Eplerenone
Indications:
o HF
o Secondary hyperaldosteronism
o Resistant hypertension
o Ascites
Pharmacokinetics/dosage form:
o Given orally
Monitoring Parameters:
o K+ level
Adverse effects:
o Gastric upset
o Hyperkalemia
o Gynecomastia and impotence
Eplerenone has a lower incidence of endocrine-related side effects (gynecomastia) due to its reduced affinity for glucocorticoid, androgen, and progesterone receptors
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21. Arteriodailator. Venodialtors. Combined mixed (balanced) dilators
3.Vasodilators
Arteriodailator.
Venodialtors.
Combined mixed (balanced) dilators
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22. 3.Vasodialtors Arteriolar VD Veinular VD
Total Peripheral resistance (TPR).
Blood pressure (DBP > SBP).
After -load on heart.
Stroke volume & COP especially in HF
Veinular VD
End Diastolic Volume (EDV).
Pre-load on the heart
COP
Bl. p. (SBP).
Renal Blood Flow (RBF).
Postural Hypotension.
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23. 3.Direct Vasodilators Hydralazine Mechanism of action:
Arterial dilator: decrease T.P.R. decrease Afterload increase S.V. & C.O.P.
Metabolized by acetylation in liver. Idiosyncrasy slow acetylators are more prone to adverse effects.
Adverse effects: Especially in Large dose & Slow Acetylators.
Orally (GIT upsets).
VD (Headache, Congestion & Flush).
Reversible Rheumatoid arthritis & Lupus erythematosis-like syndrome.
Skin rash & drug’s fever.
Peripheral neuritis.
Therapeutic Uses:
1- Hypertension Heart Failure.
hypersensitivity
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24. 3.Direct Venodilators
Venous dilator: Nitrates such as isosorbide dinitrate: decrease VR decrease EDV decrease Preload & Pulmonary congestion.
They are mentioned in details in antianginal drugs.
A fixed-dose combination of hydralazine and nitrate improves symptoms and survival in patients running on standard HF treatment (β -blocker plus ACE inhibitor or ARB)
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25. 3. Direct mixed vaso & venodialtors: Na Nitroprusside
Mechanism of action:
Nitroprusside RBCs & Endothelium NO Guanylate Cyclase cGMP:
a- Mixed Balanced (Arteriolar = Venular) VD.
b- Platelet aggregation.
Pharmacodynamics:
Used by IV Infusion. Onset : 1/2 min. Peak : 2 min. Duration : 3 min.
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26. 3. Direct mixed vaso & venodialtors: Na Nitroprusside
Therapeutic uses: a- Emergency Hypertension e.g. Hypertensive Encephalopathy. b- Emergency acute Heart Failure. Disadvantages of Nitroprusside: a- Large dose (Severe Hypotension & Shock). b- Sudden Stop (Rebound Hypertension). c- Prolonged Use especially in old age (arrhythmia, Delirium & Psychosis & DEATH) d- Teratogenic.
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27. 4. Diuretics
Prescribed For all patients with evidence of fluid retention
Do not alter disease progression or prolong survival
Just reduce symptoms & improve exercise tolerance, quality of life
reduce HF hospitalizations
Loop diuretics are the most commonly used diuretics in HF
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7/24/2019

28. 4. Diuretics: Loop Diuretics
Agents: furosemide,, toresmide & ethacrynic acid
Ethacrynic acid reserved for patient with sulfa allergy
M.O.A:
↓ plasma volume ↓ venous return to heart (↓preload) ↓ heart workload
Actions:
Relieve pulmonary congestion and peripheral edema
Reduce the symptoms of volume overload, including orthopnea and paroxysmal nocturnal dyspnea
Indications:
Reducing acute pulmonary edema and acute/chronic peripheral edema caused from heart failure or renal impairment
Hyperkalemia
Hypercalcemia
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7/24/2019

29. 6. Diuretics: Loop Diuretics
Pharmacokinetics/dosage form:
Given orally or IV
IV in emergency situation such as pulmonary edema secondary to HF
Predictable action within 2-4 hours
Monitoring Parameters:
All electrolytes (K, Na, Cl, Mg) level
Adverse effects:
Ototoxicity: Reversible or permanent hearing loss. Commonly when used in conjunction with other ototoxic drugs (for example, aminoglycoside antibiotics)
Ethacrynic acid is the most likely to cause deafness
Hyperuricemia: Furosemide and ethacrynic acid compete with uric acid for the renal secretory systems (blocking its secretion &causing or exacerbating gouty attacks)
Acute hypovolemia
Risk for hypotension, shock, and cardiac arrhythmias
Hypokalemia
Hypomagnesemia
With chronic use particularly in the elderly
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