Drugs used in Heart failure

Pathophysiology of heart failure

1. Cardiac output ↓
a) systolic disfunction⇒ cardiac output↓
typical of acute failure
b) diastolic dysfunction ⇐ hypertrophy
stiffing of myocardium
2. High-output failure
3. Symptoms: tachycardia
decreased exercise tolerance
shortness of breath
peripheral and pulmonary edema
cardiomegaly
4. Neurohumoral reflex (extrinsic) compensation
5. Myocardial hypertrophy
(intrinsic compensation)
Remodeling
Pathophysiology of cardiac performance
1) preload ↑
2) afterload ↑
3) contractility↓
4) heart rate ↑
Basic Pharmacology of Drugs Used in Congestive Heart Failure
Digitalis
1. Chemistry
a) steriod nucleus
b) unsaturated
five-membered ring
c) sugar
2. Pharmacokinetics
1) digoxin
bioavailability: antibiotics
dissolution test
renal disease

2) digitoxin
enterohepatic circulation: long

half-life
Bufadienolides
3) Pharmacodynamics
a) Mechanisms Na+-Ca+2 exchanger

site 1: Na+/K+ ATPase

site 2:Na-Ca exchanger

b) Cardiac effects
i) Mechanical effect
ventricular ejection ↑
end-systolic size↓
end-diastolic size ↓
cardiac output ↑
renal perfusion ↑
ii) Elecrical effect
At therapeutic, nontoxic serum concentration
(1) shortening action potential⇐ K conductance↑ ⇐Ca ↑
shortening of atrial and ventricular refractoriness
More toxic concentrations
(2) resting membrane potential ↓( less negative) ⇐ intracellular K ↓
⇑
sodium pump ↓
 More toxic concentrations
(3) afterpotential : intracellular calcium stores
Afterpotential in the Purkinje conducting system: bigeminy
With further toxic deterioration: tachycardia ⇒ fibrillation ⇒fatal

(4) parasympathomimetic effects (lower dose): atrial and AV nodal

(5) sympathetic outflow ↑
toxic levels
c. Effects on other organs
i) ↓ sodium pump ⇒ depolarization
ii) sympathetic tone ↓ ⇒ vascular tone ↓
iii) G-I: anorexia, nausea, vomiting, diarrhea
direct
chemoreceptor trigger zone
iv) CNS: hallucination, convulsions

d. Interactions with K, Ca and Mg

i) hypokalemia ⇒ Na+/K+ ATPase inhibition
ii) hyperkalemia ⇒ abnormal cardiac automaticity ↓
iii) hypercalcemia ⇒ arrhythmia
iv) hypomagnesemia ⇒ arrhythmia
4). Clinical uses
a) congestive heart failure: cardiac output↑⇒ sympathetic ↓
renal blood flow ↑⇒edema ↓
b) atrial arrhythmias⇐ vagomimetic actions
c) paroxysmal atrial and atrioventricular nodal tachycardia
d) contraindication: Wolff-Parkinson-White syndrome (reentrant)

5). Drug interaction

a) diuretic therapy and diarrhea: hypokalemia
b) quindine, NSAID, calcium channel blocker: tissue binding site
c) quinidine: depressed renal digoxin clearance
d) antibiotics
e) cholestyramine: digitalis absorption↓
f) hyperthyroid patient: elimination half-life↓
6). Toxicity (17-27 % hospital; 5-25 % temporary cessation)
a) visual changes or G-I disturbance
b) significant digitalis toxicity: digitalis, potassium level, EEG
c) electrolyte status: corrected
d) do not response promtly: Ca, Mg, K level
e) premature ventricular depolarization: K supplementation
brief runs of bigeminy
f) serious arrhythmias: parenteral K
lidocaine
g) very severe digitalis intoxication
antiarrhythmic: cardiac arrest (serum K↑)
temporary cardiac pacemaker catheter
digitalis antibody
cardioversion: ventricular fibrillation
2. Bipyridines (Amrinone and Milrinone)
1) Mechanisms
a) inward calcium flux↑
b) sarcoplasmic reticulum ⇒Ca ↑
c) phosphodiesterase inhibition ⇒ cAMP ↑
vasodilation, contractility
2) Acute heart failure
a) cardiac output ↑
b) pulmonary capillary wedge pressure ↓
c) peripheral vascular resistance ↓
3) Toxicity (high incidence)
nausea, vomiting, thrombocytopenia, liver enzyme changes
4) Uses
only i.v for acute heart failure or
for an exacerbation of chronic heart failure
3. Beta-Adrenoceptor Stimulant
Dobutamine
1) β1-selective agents
2) cardiac output ↑
ventricular filling pressure ↓
3) angina or arrhythmia
4) tachyphylaxis
5) Intermittent dobutamine infusion may benefit some
patients with chronic heart failure
Drugs without positive inotropic effects used in heart failure
↓
4. Diuretics
1) reduce salt and water retention ⇒ventricular preload ↓
edema ↓ and cardiac size ↓ ⇒pump function ↑
2) spironolactone: aldosterone antagonist
aldosterone ⇒ myocardial and vascular fibrosis
baroreceptor reflex dysfunction
5. Angiotensin-Converting Enzymes Inhibitors
1) angiotensin II in the compensatory response to failure
2) peripheral resistance ↓ ⇒ afterload ↓
3) salt and water retention ↓ ⇒ preload ↓ ⇒
4) angiotensin’s presynaptic effect ↓ ⇒ sympathetic activity ↓
5) long-term remodeling of the heart and vessels ↓
(mortality and morbidity)
6) ahead of digitalis in the treatment of chronic failure
6. Vasodilator: hydralazine and isosorbide dinitrate
preload
afterload

brain natriuretic peptide (nesiritide):vasodlator

diuresis
acute cardiac failure

7. Beta-Adrenoceptor Blockers
attenuation of the adverse effect of high concentrations of
catecholamine, up-regulation of beta receptors, decreased

heart rate, and reduced remodeling through inhibition of

the mitogenic activity of catecholamines
 Management
Clinical Pharmacology of Drugs Used in heart Failure of
Chronic Heart Failure
Management of Chronic heart Failure
Management of Acute Heart Failure
OBJECTIVES
1. Describe the strategies and list the major groups used in the
treatment of congestive heart failure.
2. Describe the probable mechanism of action of digitalis.
3. Describe the nature and mechanism of digitalis’s toxic effect on
the heart.
4. List some positive inotropic drugs that have been investigated as
digitalis substitutes.
5. Describe the beneficial effects of diuretics, vasodilators,
ACE inhibitors, and other drugs that lack positive inotropic
effects in congestive heart failure.