FARMAKOLOGI

OBAT-OBAT GAGAL JANTUNG

Pendahuluan
Gagal jantung ?? penyebab ??
Penyebab : jantung tidak cukup dlm memompa darah ke sirkulasi
dibandingkan dengan kebutuhan tubuh
Penyakit gagal jantung kongestif  penyebab kematian utama 
mortalitas 50%.
Penyebab utama gagal jantung  aterosklerosis koroner.
Terapi obat ditujukan untuk menurunkan konsumsi oksigen 
1. menurunkan heart rate,
2. menurunkan tekanan dinding pembuluh darah ventrikel
(sistole dan diastole),
3. memperbaiki aliran darah koroner,
4. mencegah trombosis koroner.
Guyton et al, 2000
MFMER, 2007
Gagal Jantung (Patofisiologi)

Maron BA, Rocco, 2011

Gagal Jantung (Patofisiologi)
Disfungsi miokardial (muscular tissue of the heart)  penurunan
curah jantung menyebabkan aktivasi sistem neurohormonal 
sistem syaraf simpatik dan sistem renin-angiotensin
Hal ini merupakan kompensasi kondisi gagal jantung 
memelihara perfusi darah menuju organ penting dg :
1. meningkatkan preload ventrikel kanan,
2. merangsang kontraksi miokardial dan
3. meningkatkan tonus arteri.
Secara akut, mekanisme tersebut akan meningkatan curah jantung
 memungkinkan jantung beroperasi pada volume distole yang
lebih besar  volume stroke jantung dapat meningkat.
Secara bersamaan, vasokonstriksi perifer menyebabkan
redistribusi regional curah jantung ke organ-organ penting.
Gagal Jantung (Patofisiologi)
Dampak kompensasi??
Mekanisme kompensasi tersebut justru memperparah progres
penyakit  peningkatan tekanan dinding sistole dan diastole 
gangguan miokardial dan induksi hipertropi.
Aktivasi neurohormonal  konstriksi pembuluh darah vena dan
arteri :
1. Konstriksi vena  meningkatkan afterload ventrikel kiri
2. Konstriksi arteri  meningkatkan preload 
memperparah tekanan dinding distole dan diastole
Efektor neurohormonal yaitu NE dan angiotensin 2  beraksi pada
miokardial  remodeling  myocyte apoptosis, abnormal gene
expression, dan perubahan pada matrik ekstraseluler.
Terapi Gagal Jantung
ACE inhibitor Diuretika Digitalis

Menurunkan beban Mengkontrol Meningkatkan

kerja jantung kelebihan kontraktilitas
akumulasi cairan
pada gagal jantung
Menurunkan Menurunkan
symptom gagal symptom gagal
jantung jantung
Gagal jantung
terkait dengan
retensi air/Na+
Nitrat Pada kondisi
(isosorbid dinitrat, parah, dopamin &
nitroprusida);  dobutamin dpt
blocker digunakan (i.v.)
Cardiac Glycosides
Dideskripsikan pertama kali oleh William Withering thn 1785 
monograf efikasi dan toksisitas tanaman Digitalis purpurea.
Senyawa aktif  digitoksin dan digoksin.
Juga dijumpai pada tanaman Digitalis lanata.
Strophanthus grantus  ouabain
Th 1990, digoksin paling sering digunakan secara klinik  profil
farmakokinetika lebih baik, penetapan kadar obat dalam darah
lebih mudah.
Efek : memperbaiki kontraktilitas miokardial (otot jantung)
Glikosida jantung  low therapeutic index (= LD50/ED50)
low therapeutic index kons. obat dlm plasma utk menyebabkan
toksisitas sedikit lebih tinggi dari dosis terapinya
Indeks terapi glikosida  1.6 – 2.5
Mekanisme aksi
Penghambatan Na+/K+-ATPase
Semua glikosida jantung  poten dan selektif menghambat
transpor aktif Na+ dan K+ menembus membran sel.
Glikosida jantung  mengikat sisi spesifik pada subunit alfa
Na+/K+-ATPase.
Pada sisi lain,
Na+ dan Ca2+ masuk sel otot jantung selama proses depolarisasi
Masuknya Ca2+  kontraksi  kompensasi aktivasi Ca2+-ATPase
retikulum sarkoplasma (SERCA2), Na+/Ca2+-exchanger, Ca2+-ATPase
membran sel sarcolemma.
Penghambatan Na+/K+-ATPase  penurunan ekstruksi Na+ 
kadar Na+ dalam sel meningkat  menurunkan kemampuan
Na+/Ca2+-exchanger untuk mengekstruksi Ca2+ selama repolarisasi
sel otot (myocyte).
Penurunan efluks Ca2+ dan masuknya Ca2+  akumulasi Ca2+ dalam
sel otot jantung  kontraksi.
Mekanisme aksi
Penghambatan Na+/K+-ATPase

Hall JE, Guyton AC (2006).

Farmakokinetika
DIGOKSIN
T1/2 eliminasi 36-48 jam pada pasien dengan fungsi ginjal
normal  dosis sehari sekali.
Ekskresi obat melalui ginjal dan mostly dlm bentuk utuh
Pada pasien gagal jantung kongestif dengan terapi
vasodilator atau agen simpatomimetik  meningkatkan
kliren digoksin.
Pada pasien gagal ginjal kronis  t1/2 eliminasi 3-5 hari
tidak dipengauhi oleh hemodialisa.
Bioavailabilitas dalam bentuk tablet 75%.

Bauer LA, 2009

Farmakokinetika
Digoxin is usually given orally, but can also be given by IV
injection in urgent situation
Some metabolism may occur within the GI tract.
Peak serum levels occur within 1 hour
Protein binding: 20-30% to albumin.
Enterohepatic cycling occurs.
Digoksin tidak dapat menembus plasenta.
Excretion involves P-glycoprotein, tubular secretion is inhibited
by hypokalemia, spironolactone, quinidine, verapamil, and
amiodarone.
Pemberian parenteral  intravena  jika dosis oral kurang baik.
Pemberian im  absorpsi eratik  tidak direkomendasikan.
Wallace JH, 2006
Farmakokinetika
DIGITOKSIN
Didapatkan dari daun
digitalis, bersifat kurang
polar.
Diekskresi secara lambat.
Bioavailabilitas oral hampir
100%.
QUOABAIN
Larut dalam air
Beraksi secara cepat
Bioavailabilitas oral kurang
bagus  pemberian iv
Ekskresi melalui ginjal

Terikat kuat protein. T1/2 eliminasi : 18-24 jam

Metabolisme ekstensif di hati

T1/2 eliminasi : 4-7 hari
 Adrenergic and Dopaminergic
Agonists
Dopamine and dobutamine  agen inotropik positif 
terapi jangka pendek.

Obat tsb beraksi  stimulasi cardiac myocyte dopamine D1

receptor dan  adrenergic receptor  stimulasi Gs-adenylyl
cyclase-cyclic AMP-PKA pathway.

Catalytic subunit of PKA phosphorylates a number of

substrates that enhance Ca2+-dependent contraction.

Contoh lain : Isoproterenol, epinephrine, and norepinephrine

 Adrenergic and Dopaminergic
Agonists
Dopamine
The pharmacological and hemodynamic effects  dose dependent.
At low doses causes vasodilation 
1. stimulating dopaminergic receptors on smooth muscle  causing
cyclic AMP-dependent relaxation
2. stimulating presynaptic D2 receptors on sympathetic nerves in the
peripheral circulation  inhibiting norepinephrine release and
reducing  adrenergic stimulation of vascular smooth muscle
At intermediate infusion rates  directly stimulates  receptors on the
heart and vascular sympathetic neurons enhancing cardiac
contractility (not heart rate) and neural norepinephrine release.
At higher infusion rates  peripheral arterial and venous constriction
occur  mediated by  adrenergic receptor stimulation.
 Adrenergic and Dopaminergic
Agonists
Dobutamin
Choice for the management of patients with systolic dysfunction
and CHF.
Principal hemodynamic effect  an increase in stroke volume due
to its positive inotropic action.
Dobutamine does not activate dopaminergic receptors.
If cardiac output is significantly increased  heart rate may
decline secondary to reflex withdrawal of sympathetic tone.
The major side effects  excessive tachycardia and arrhythmias
 require a reduction in dosage.
Tolerance may occur after prolonged use  requiring substitution
of alternative drug such as a class III phosphodiesterase inhibitor.
 Adrenergic and Dopaminergic
Agonists
Phosphodiesterase Inhibitors

Cyclic AMP-phosphodiesterase (PDE) inhibitors  reduce the

degradation of cellular cyclic AMP
Elevated cyclic AMP occur in response to a stimulator of
adenylyl cyclase activity.
In the heart, the result is positive inotropism.
In the peripheral vasculature, the result is dilation of both
resistance and capacitance vessels, leading to reduction of both
afterload and preload.
Contoh : theophylline and caffeine  concomitant side effects.
Amrinone, milrinone, and other PDE inhibitors with isoenzyme
selectivity largely alleviate these side effects
Efek Phosphodiesterase Inhibitors pada Jantung

Medscape, 2011
R. Lane Brown; et al,2006
Efek Phosphodiesterase Inhibitors pada Otot Polos

Calcium-calmodulin activates myosin light chain kinase (MLCK), an enzyme that

is capable of phosphorylating myosin light chains (MLC) in the presence of
ATP. Myosin light chains are 20-kD regulatory subunits found on the myosin
heads. MLC phosphorylation leads to cross-bridge formation between the myosin
heads and the actin filaments, and hence, smooth muscle contraction.
Richard E, 2014
Lobato EB, et al., 2006
Kadam VJ., et al, 2009
Hofer, et al, 2007
Diuretics
Ginjal pegang peran sentral hemodynamic,
hormonal, dan autonomic responses pada myocardial failure.
Retention of Na+ and water dan expansion of the
extracellular fluid volume  heart to operate at higher end-
diastolic volumes  maintain LV stroke volume.
Increase in end-diastolic volume higher end-diastolic
filling pressures, increased ventricular chamber dimensions,
and elevated wall stress  Cardiac output
Diuretics reduce extracellular fluid volume and ventricular
filling pressure (or “preload”)  penurunan cardiac output
Patient  limit dietary intake of NaCl  tolerate moderate
reductions in salt intake (2–3 g/day total intake).
Diuretics
LOOP DIURETICS
• Contoh : Furosemide (LASIX), bumetanide (BUMEX), and
torsemide (DEMADEX)
• The increased risk of ototoxicity, ethacrynic acid (EDECRIN)
 patients who are allergic to sulfonamides or nterstitial
nephritis on alternative drugs.

THIAZIDE DIURETICS
• most frequently used in the treatment of
hypertensionmereka memainkan peran yang lebih terbatas
dalam pengobatan
• CHF
• associated with a greater degree of K+ wasting for
comparable volume reduction than are loop diuretics.
Diuretics
K+-SPARING DIURETICS
• Act in the collecting duct of the nephron
• Contoh : amiloride, triamterene, spironolactone,
eplerenone.
• These agents are relatively weak diuretics and therefore
are not effective for volume reduction.
• Historically, these agents have been used to limit renal K+
and Mg2+ wasting and/or to augment the diuretic response
to other agents.
Vasodilators
Vasodilators  help widen, or dilate, blood vessels.
This reduces blood pressure and makes it easier for the heart
to pump blood.
When you have heart failure  your heart does not pump as
well  opening narrowed blood vessels is important.
This reduces how hard your heart needs to work.
It may help keep blood from backing up in your heart and
lungs.
Vasodilators

Mae LS, 2014

Hydralazine
 Hydralazine binds to and activates gated potassium channels
on vascular smooth muscle.
 The result is an efflux of potassium and a subsequent
hyperpolarization of the cell.
 This prevents calcium-mediated activation and constriction of
the smooth muscle, resulting in vasodilation.
 However, this induced vasodilation triggers the baroreflex
resulting in tachycardia and vasoconstriction.
 Hydralazine is therefore not a great candidate for control of
hypertension alone. It is often co-administered with a beta
blocker to mitigate the effects of the baroreflex.
 Hydralazine requires the endothelium to provide NO (nitric
oxide) thus only provides the effects of NO in vivo with
functional endothelium. It will not work to vasodilate in vitro in
an isolated blood vessel.
Gharaibeh M, 2009
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