CONGESTIVE HEART FAILURE

TIM DOSEN FARMAKOLOGI 3

 CONGESTIVE HEART FAILURE

- Heart failure occurs when

cardiac output is
inadequate to provide the
oxygen needed by the
body, or
- When the heart can no
longer pump enough
blood to meet the
demands of the body
GOALOF THERAPY

• Treatment of CHF is directed at two somewhat different goals:

(1) reducing symptoms and slowing progression as much as possible during relatively
stable periods and
(2) managing acute episodes of decompensated failure.
Source : Katzung, 2015
• Large clinical trials have shown that therapy directed at noncardiac targets is more
valuable in the long-term treatment of heart failure than traditional positive inotropic
agents (cardiac glycosides [digitalis]).
• Extensive trials have shown that angiotensin-converting enzyme (ACE) inhibitors,
angiotensin receptor blockers (ARBs), certain β blockers, aldosterone receptor
antagonists, and combined hydralazine-nitrate therapy are the only agents in current use
that actually prolong life in patients with chronic heart failure. These strategies are useful
in both systolic and diastolic failure.
• Positive inotropic drugs, on the other hand, are helpful mainly in acute systolic failure.
Cardiac glycosides also reduce symptoms in chronic systolic heart failure. In large clinical
trials to date, other positive inotropic drugs have usually reduced survival in chronic
failure or had no benefit, and their use is discouraged.
OBAT GAGAL JANTUNG :
A. ACE inhibitor
B. AT1 bloker
C. B-Bloker
D. Diuretik
E. Antagonis aldosterone
F. KARDIOTONIK : Digitalis
KARDIOTONIK

• Adalah : obat-obat dengan khasiat memperkuat kontraktilitas otot jantung (efek inotropik
positif). Terutama digunakan pada gagal jantung (dekompensasi) untuk memperbaiki
fungsi pompa jantung
Kelompok kardiotonik :
• Glikosida jantung : digoksin
• Dopaminergik : dopamine, dobutamin, epinefrin
• Penghambat fosfodiesterase : amrinon
1. DIGOKSIN

• Digoksin
• Berkhasiat : efek inotropik positif yakni memperkuat
kontraksi jantung, efek chronotrop negatif (mengurangi
frekuensi denyut jantung)
• Indikasi : dekompensasi jantung pada gagal jantung
DIGITALIS : ENHANCEMENT OF
CONTRACTILITY
(CARDIAC GLYCOSIDES)
Digitalis purpurea :
• Digoxin
• Digitoxin
FARMAKOKINETIKA DIGOXIN

• Waktu Paruh Digoxin pendek.

• Tidak dimetabolisme
• Diabsorbsi pada GI
• Ikatannya dengan protein plasma kecil dibanding digitoxin
GLIKOSIDA JANTUNG
Mekanisme : Meningkatkan kontraktilitas myocardium dengan
menghambat pompa Na+ –K+ -ATPase
 me↑ Ca intraseluler  kontraksi serabut miokard lebih efesien

Digitalis memp. 3 khasiat pd miokard:

1. Kerja inotropik positip (me↑ kontraksi miokard)
2. Konotropik negatif (memperlambat denyut )
3. Dromotropik negatif (me- hantaran sel2 jantung)
Schematic diagram of a cardiac muscle sarcomere,
with sites of action of several drugs that alter
contractility. Na+/K+- ATPase, the sodium pump, is
the site of action of cardiac glycosides. NCX is the
sodium-calcium exchanger. Cav-L is the voltage-
gated, L-type calcium channel. SERCA (sarcoplasmic
endoplasmic reticulum Ca2+-ATPase) is a calcium
transporter ATPase that pumps calcium into the
sarcoplasmic reticulum. CalS is calcium bound to
calsequestrin, a high-capacity Ca2+-binding protein.
RyR (ryanodine RyR2 receptor) is a calcium-
activated calcium channel in the membrane of the
SR that is triggered to release stored calcium. Z is
the Z- line, which delimits the sarcomere. Calcium
sensitizers act at the actin-troponin-tropomyosin
complex where activator calcium brings about the
contractile interaction of actin and myosin. Black
arrows represent processes that initiate contraction
or support basal tone. Green arrows represent
processes that promote relaxation.
• Wanita hamil dan ibu menyusui : boleh menggunakan
digoksin dalam dosis normal
• Dosis digoksin : oral 0,25-0,75 mg sehari ac selama 1
minggu
YANG PERLU DIPERHATIKAN
• Glikosida Jantung Index terapinya sempit

• Toksisitas Glikosida Jantung banyak terjadi pada pasien dg level serum potasium
rendah.
Krn banyak pasien heart failure diberi digoxin & Diuretik

Cardiac glycosides affect all excitable tissues,

• Toksisitas yg dpt terjadi : including smooth muscle and the CNS. The
- Aritmia gastrointestinal tract is the most common
site of digitalis toxicity outside the heart.
- Anoreksia, nausea & diare
The effects include anorexia, nausea,
- Drowsiness & fatigue vomiting, and diarrhea. This toxicity is
- Visual disturbance caused in part by direct effects on the
- Life-threatening
gastrointestinal tract and in part by CNS
actions.
REDUCTION OF CARDIAC WORKLOAD

Pharmacologically : Vasodilator
- Angiotensin-converting enzyme (ACE) inhibitors
- Antagonis Angiotensin II Receptor (ARB)
- Vasodilator lainnya.
JENIS

ACE Inhibitor ARB

Benazepril
Captopril
Enalapril Candesartan
Fosinopril Eprosartan
Lisinopril Irbesartan
Moexipril Iosartan
Quinapril Valsartan
Ramipril
ACEI

ARB
ACE inhibitors
CONTROL OF EXCESSIVE FLUID

• Heart failure berhubungan dg retensi Na & air

• Penanganannya :
- Lower dietary intake of sodium
- Diuretik

Diuretics are almost always used to control excess fluid accumulation in heart failure
 2. DOPAMINERGIK (SYMPATHOMIMETICS)

• Dobutamine digunakan untuk meningkatkan cardiac output pada heart falure

• Mechanism of action : Dobutamine activates adenylate cyclase through direct stimulation of β-adrenergic
receptors (selective β1) , thus catalyzing the conversion of adenosine triphosphate to cAMP  produces
an increase in cardiac output together with a decrease in ventricular filling pressure.
• Dapat digunakan pada penanganan shock
• Dobutamine adalah Beta 1 agonis
• Dengan dosis sedang dapat meningkatkan kontraktilitas jantung tanpa mempengaruhi tekanan darah atau
heart rate.
• Only given intravenously (IV)
 2. DOPAMINERGIK (SYMPATHOMIMETICS)

• Dopamine, an endogenous catecholamine that is the immediate precursor of norepinephrine, is a

sympathomimetic agent with prominent dopaminergic and β1-adrenergic effects at low to moderate
doses and α-adrenergic effects at high doses
• Epinephrine is an endogenous catecholamine that is the active principle of the adrenal medulla;
epinephrine acts directly on both α- and β-adrenergic receptors.
 3. PENGHAMBAT FOSFODIESTERASE

• Major efforts are being made to find safer positive inotropic agents because cardiac glycosides have an
extremely narrow therapeutic index and may not decrease mortality in chronic heart failure
• Penghambat fosfodiesterase termasuk inotropik positif selain digitalis
• Milrinone and amrinone are a bipyridine compound that inhibits phosphodiesterase isozyme 3 (PDE-3).
It is active orally as well as parenterally but is available only in parenteral form. It has an elimination half-
life of 3-6 hours, with 10-40% being excreted in the urine
• milrinone reduces degradation of cAMP by inhibiting phosphodiesterase. Increased intracellular cAMP
enhances phospholipase (and subsequently phosphorylase) activity, increasing the rate and extent of
calcium influx during systole and enhancing contractility. Additionally, cAMP enhances reuptake of
calcium by the sarcoplasmic reticulum during diastole, improving active relaxation
PENGHAMBAT FOSFODIESTERASE

• The bipyridines  increase myocardial contractility (by increasing inward calcium flux in
the heart during the action potential)
• Bipyridines also alter the intracellular movements of calcium by influencing the
sarcoplasmic reticulum. In addition, they have an important vasodilating effect.
• Inhibition of phosphodiesterase results in an increase in cAMP and the increase in
contractility and vasodilation.
• Milrinone is now used only intravenously and only for acute heart failure or severe
exacerbation of chronic heart failure.