Drugs used in treatment of Heart failure II Dr. Asmaa Fady PhD., MSC., M.B, B.Ch اسم ورقم المقرر – Course Name and No. 7/24/2019

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

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 اسم ورقم المقرر – Course Name and No. 7/24/2019

Classification of heart failure Based on the severity (body compensation): 1. Compensated (Chronic) heart failure [CHF] 2. Decompensated (Acute) heart failure [AHF]= emergency condition اسم ورقم المقرر – Course Name and No. 7/24/2019

= SV * HR اسم ورقم المقرر – Course Name and No. 7/24/2019

Generalized VC اسم ورقم المقرر – Course Name and No. 7/24/2019

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 اسم ورقم المقرر – Course Name and No. 7/24/2019

Drug therapy for heart failure +ve inotropes اسم ورقم المقرر – Course Name and No. 7/24/2019

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. اسم ورقم المقرر – Course Name and No. 7/24/2019

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 اسم ورقم المقرر – Course Name and No. 7/24/2019

2. Cardio protective drugs a. Angiotensin converting enzyme inhibitors (ACEI). b. Angiotensin II Receptor Antagonists (ARBs). c. Beta Blockers. d. Aldosterone Antagonists اسم ورقم المقرر – Course Name and No. 7/24/2019

Renin Angiotensin Aldosteron System (RAAS) Antagonists اسم ورقم المقرر – Course Name and No. 7/24/2019

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. اسم ورقم المقرر – Course Name and No. 7/24/2019

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 اسم ورقم المقرر – Course Name and No. 7/24/2019

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. اسم ورقم المقرر – Course Name and No. 7/24/2019

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 اسم ورقم المقرر – Course Name and No. 7/24/2019

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 اسم ورقم المقرر – Course Name and No. 7/24/2019

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. اسم ورقم المقرر – Course Name and No. 7/24/2019

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. اسم ورقم المقرر – Course Name and No. 7/24/2019

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 اسم ورقم المقرر – Course Name and No. 7/24/2019

Arteriodailator. Venodialtors. Combined mixed (balanced) dilators 3.Vasodilators Arteriodailator. Venodialtors. Combined mixed (balanced) dilators اسم ورقم المقرر – Course Name and No. 7/24/2019

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. اسم ورقم المقرر – Course Name and No. 7/24/2019

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 2- Heart Failure. hypersensitivity اسم ورقم المقرر – Course Name and No. 7/24/2019

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) اسم ورقم المقرر – Course Name and No. 7/24/2019

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. اسم ورقم المقرر – Course Name and No. 7/24/2019

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. اسم ورقم المقرر – Course Name and No. 7/24/2019

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 اسم ورقم المقرر – Course Name and No. 7/24/2019

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 اسم ورقم المقرر – Course Name and No. 7/24/2019

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 اسم ورقم المقرر – Course Name and No. 7/24/2019

اسم ورقم المقرر – Course Name and No. 7/24/2019