Terapi Farmakologik

gagal Jantung
FK UNSRAT
September 2020

1
 • Tujuan pengobatan, Jika penyebab dasar
tidak dpt dikoreksi :
A. Cegah perburukan fungsi jantung 
Tujuan Primer :
hambat remodelling miokard 
• Mencegah terjadinya gagal jantung mengurangi mortalitas
dgn cara mengobati kondisi-kondisi B. Mengurangi gejala-gejala gagal jantung 
yg menuju terjadinya fafal jantung, memperbaiki kualitas hidup
terutama hipertensi dan.atau • Tujuan A (gagal jantung kronik) 
penyakit arteri koroner. penghambat ACE & -bloker (mengurangi
• Jika disfungsi miokard sudah beban kerja jantung)
terjadi : • Tujuan B (gagal jantung akut)  pengurangan
• mengobati/menghilangkan penyebab overload cairandiuretik; penurunan
dasarnya, jika mungkin (mis: iskemia, resistensi perifer  vasodilator; peningkatan
penyakit tiroid,alkohol, obat) kontraktilitas miokard  inotropik
2
 Obat pada gagal jantung
Ace Inhibitor Angiotensin Aldosterone -adrenoceptor Diuretic Direct vaso and Inotropic
receptor antangonists blockers venodlators
blockers
Captopril Candesartan Eplerenone Bisoprolol Bumetanide Hydralazine Digoxin
Enalapril Losartan Spironalactone Carvedilol Furosemide Isosorbide Dobutamine
dinitrate
Fosinopril Telmisartan Metoprolol Metolazone FDC Milrinone
succinate Hydralazine/iso
sorbide
dinitrate
Lisinopril Valsartan Metoprolol Torsemide
Tartrate
Quinapril
Ramipril

3
 Strategi terapi – HF
• Pembatasan cairan (less than 1.5 to 2 L daily) & Garam(< 2000 mg/d)
• Pengobatan faktor komorbid
• Penggunaan diuretic, penghambat renin–angiotensin–aldosterone system &
penghambat sistem saraf simpatis.
• Penggunaan obat inotropic pd pasien rawat inap dengan tanda & gejala tipe
akut HF.
• Menghindari obat – obat pencetus HF : nonsteroidal anti-inflammatory
drugs (NSAIDs), alkohol, nondihydropyridine calcium channel blockers, obat-
obat antiarrhythmic

4
Ion Movement during the contraction of cardiac muscle

5
 HF – aktivasi RAA

1) increased renin release by juxtaglomerular cells in renal afferent arterioles

due to diminished renal perfusion pressure produced by the failing heart
2) Renin release by juxtaglomerular cells promoted by sympathetic stimulation
& activation of β receptors.
1) The production of angiotensin II, a potent vasoconstrictor&the
subsequent stimulation of aldosterone release that causes salt& water
retention  increases in both preload&afterload that are characteristic
of the failing heart.
2) In addition, high levels of angiotensin II & of aldosterone have direct
detrimental effects on the cardiac muscle, favoring remodeling, fibrosis
& inflammatory changes.

6
Penghambat renin-angiotensin-aldosteron
A. Penghambat ACE (ACE-Inhibitor)

B. Angiontensin receptor blockers

C. Aldosterone antagonis

7
 A. Penghambat ACE (ACE-Inhibitor)

• Hambat konversi angiotensin 1 (Ang 1)  Angiotensin II (Ang II)

• Stimulasi reseptor AT1  vasokonstriksi, stimulasi & pelepasan aldosteron,
pe↑aktivitas simpatis & hipertrofi miokard;
• aldosteron menyebabkan reabsorpsi Na & air ditubulus ginjal, sedangkan aktivitas simpatis
sebabkan sekresi renin dari sel jukstaglomerular di ginjal
• Reseptor AT2 memperantarai stimulasi apoptosis & antiproliferasi
• Penghambat ACE dgn mengurangi pembentukan Ang II  hambat aktivitas Ang II
di reseptor AT1 maupun AT2
• Pengurangan hipertrofi miokard & pe ↓ preload jantung  hambat progresi
remodelling jantung
8
 Penghambat ACE

• Pe↓ aktivasi neurohormonal endogen (Ang II, aldosteron,norepinefrin) 

mengurangi efek langsungnya dlm menstimulasi remodelling jantung
• Enzim ACE  kinase II  penghambat ACE  hambat degradasi bradikinin 
kadar bradikinin yg terbentuk lokal di endotel vaskuler ↑
• Bradikinin bekerja lokal pd reseptor BK2 di sel endotel  Nitric oxide (NO) &
Prostasiklin (PGI2) merupakan vasodilator, antiagregasi trombosit & antiproliferasi
• ES :
• 1).batuk kering (insidens sampai >30%), diduga terjadi pd jalur KKP (kalikrein-bradikinin-
prostaglandin) dgn melibatkan bradikinin, substansi P, prostaglandin & leukotrien;
• 2)Angioedema (insiden 0.1-1%) diduga akibat akumulasi bradikinin

9
 Indications:
Penghambat ACE • Considered for patients with asymptomatic &
symptomatic HFrEF.
• Actions on the heart: • Importantly : indicated for patients with all stages
of left ventricular failure.
• ACE inhibitors decrease vascular
resistance (afterload) & venous tone • Patients with the lowest ejection fraction show the
(preload), resulting in increased greatest benefit from use of ACE inhibitors.
cardiac output. • Depending on the severity of HF, ACE inhibitors
may be used in combination with diuretics, β-
• ACE inhibitors also blunt the usual blockers, digoxin, aldosterone antagonists, and
angiotensin II–mediated increase in hydralazine/isosorbide dinitrate fixed-dose
epinephrine and aldosterone seen in combination.
HF.
• Patients who have had a recent myocardial
• ACE inhibitors improve clinical signs infarction or are at high risk for a cardiovascular
and symptoms of HF & have been event also benefit from long-term ACE inhibitor
shown to significantly improve patient therapy.
survival in HF • ACE inhibitors are also used for the treatment of
hypertension 10
 Mekanisme kerja
penghambat ACE (ACE-inhibitors)

11
 • Adverse effects:
Penghambat ACE
• Postural hypotension, renal insufficiency,
hyperkalemia, a persistent dry cough &
• Pharmacokinetics: angioedema (rare).
• adequately absorbed following oral • Potassium levels must be monitored,
administration.
particularly with concurrent use of
• Food may decrease the absorption of potassium supplements, potassium-sparing
captopril, so it should be taken on an empty diuretics, or aldosterone antagonists due to
stomach. risk of hyperkalemia.
• Except for captopril, ACE inhibitors are • Serum creatinine levels should also be
prodrugs that require activation by monitored, particularly in patients with
hydrolysis via hepatic enzymes. underlying renal disease.
• Renal elimination of the active moiety is
important for most ACE inhibitors except
• The potential for symptomatic hypotension
fosinopril. with ACE inhibitors is much more common if
used concomitantly with a diuretic.
• T ½ plasma of active compounds vary from 2
to 12 hours, although the inhibition of ACE • ACE inhibitors are teratogenic & should not
may be much longer. be used in pregnant women. 12
 Effect of enalapril on the mortality
of patients with symptomatic heart failure with reduced
ejection fraction

Dikutip dari : Pharmacology by Lippincot 6th edition.2015

13
 B.Angiotensin receptor Blocker

• Angiotensin receptor blockers (ARBs) are orally active compounds that are
competitive antagonists of the angiotensin II type 1 receptor.
• ARBs have the advantage of more complete blockade of angiotensin II action,
because ACE inhibitors inhibit only one enzyme responsible for the production of
angiotensin II.
• Further, ARBs do not affect bradykinin levels.
• Although ARBs have actions similar to those of ACE inhibitors, they are not therapeutically
identical.
• Even so, ARBs are a substitute for ACE inhibitors in those patients who cannot tolerate the
latter.
14
Angiotensin receptor Blocker
Actions on the cardiovascular system
• Although ARBs have a different mechanism of action than ACE
inhibitors, their actions on preload and afterload are similar.
• Their use in HF is mainly as a substitute for ACE inhibitors in those
patients with severe cough or angioedema, which are thought to be
mediated by elevated bradykinin levels.
• ARBs are also used in the treatment of hypertension.

15
Pharmacokinetics:
• All the drugs are orally active and are
dosed once-daily, with the exception of Adverse effects:
valsartan which is twice a day.
• ARBs have an adverse effect and
• They are highly plasma protein bound and, drug interaction profile similar to
except for candesartan have large volumes that of ACE inhibitors.
of distribution.
• However, the ARBs have a lower
• Losartan, the prototype of the class,
differs in that it undergoes extensive first-
incidence of cough and
pass hepatic metabolism, including angioedema.
conversion to its active metabolite. • Like ACE inhibitors, ARBs are
• The other drugs have inactive metabolites. contraindicated in pregnancy.
• Elimination of metabolites and parent
compounds occurs in urine and feces.
16
 C. Aldosterone antagonis
• Patients with advanced heart disease have elevated levels of aldosterone due to
angiotensin II stimulation and reduced hepatic clearance of the hormone.
• Spironolactone is a direct antagonist of aldosterone, thereby preventing salt
retention, myocardial hypertrophy, and hypokalemia.
• Eplerenone is a competitive antagonist of aldosterone at mineralocorticoid
receptors.
• Although similar in action to spironolactone at the mineralocorticoid receptor,
eplerenone has a lower incidence of endocrine-related side effects due to its
reduced affinity for glucocorticoid, androgen, and progesterone receptors.
• Aldosterone antagonists are indicated in patients with more severe stages of
HFrEF or HFrEF and recent myocardial infarction.
17
Antagonis aldosteron

• Aldosteron menyebabkan :
• Retensi Na & air serta eksresi K dan Mg
• Retensi Na & air  edema & peningkatan preload jantung
• Aldosteron memacu remodelling & disfungsi ventrikel melalui preload
& efek lgsg  fibrosis miokard & proliferasi fibroblas

18
 Antagonis aldosteron
• Direkomendasikan utk ditambahkan pada : • Periksa kadar K serum (harus ≤5.0
a) Penghambat ACE & diuretik kuat pada mmol/L); Kreatinin harus ≤2.0-2.5
gagal jantung lanjut (NYHA kelas III-IV) mg/dL atau klirens kreatinin > 30
dengan disfungsi sistolik (fraksi ejeksi mL/mnt
≤35%) utk mengurangi mortalitas &
morbiditas (terbukti utk spironolakton) • Pemberian dengan dosis awal yg
b) Penghambat ACE & -bloker pd gagal rendah: Spironolakton 12,5 mg,
jantung setelah infark miokard dgn eplerenon 25 mg, dosis dpt
disfungsi sistolik ventrikel kiri (fraksi ditingkatkan  spironolkaton 25
ejeksi ≤40%) & tanda-tanda gagal jantung mg& eplerenon 50 mg, jika
atau diabetes utk mengurangi mortalitas diperlukan
&morbiditas (terbukti utk eplerenon)

19
 -bloker
Mekanisme kerja
• Aktivasi simpatis  mengaktifkan sistem • Pe↑ denyut jtg & kontraktilitas miokard 
renin-angiotensin-aldosteron (RAA). iskemia miokard relatif pe ↑ kebutuhan O2
miokard disertai dgn berkurangya pasokan O2
• Renin disekresi oleh sel jukstaglomerular miokard
di ginjal melalui stimulasi reseptor
• Iskemia miokardperlambatan konduksi
adrenergik 1
jtgaritmia jantung
• Selanjutnya aktivitas sistem simpatis
• Gagal jtg sistolik  mengurangi kejadian
maupun sistem RAA akan mengakibatkan iskemia miokard, mengurangi stimulasi sel-sel
hipertrofi miokard melalui efek automatik jantung&efek antiaritmia lain
vasokonstriksi perifer (arteri&vena) & kurangi risiko aritmia jtg
retensi Na dan air oleh ginjal
• Hambat pelepasam renin hambat aktivasi
• Sedangkan vasokonstriksi koroner  sistem RAApe↓ hipertrofi miokard,
↓pasokan darah pd dinding ventrikel yg apoptosis&fibrosis miokard,remodelling
hipertrofi  iskemia miokard miokardperlambat progresi gagal jantung
Perlambat perburukan kondisi klinik
20
-bloker

Indikasi Kontra indikasi

• Penggunaan rutin pd psn gagal • Asma bronkial,
jantung ringan & sedang(NYHA • Blok AV derajat 2-3
kelas II-III) yg stabil dgn fraksi
ejeksi<35%-45% • Bradikardia atau hipotensi yg
simtomatik
• Etiologi iskemik maupun non
iskemik dan diuretik, bersama • Hati-hati pada psn dgn gejala-
penghambat ACE (atau gejala yg lebih parah (NYHA kelas
antagonis AII) jika diperlukan IIIB & IV)
untuk mengurangi gejala ()ber
21
 -bloker

Dosis Keadan psn awal terapi

• Dimulai dosis sangat rendah, a) Retensi cairan & memburuknya
biasanya 1/10 dosis target, gejala”  tingkatkan dosis diuretik
ditingkatkan perlahan dgn supervisi b) Hipotensi,bradikardi  kurangi
ketat dosis target (dosis dosis
pemeliharaan terbukti efektif pd uji
klinik yg besar) c) Setelah psn stabil, tingkatkan
kembali dosis
• Kecepatan titrasi disesuaikan dgn
respon pasien, biasanya 2x lipat
setiap 1-2 minggu pd psn rwt jln
22
 Dosis awal, dosis target & titrasi dosis -bloker yg terbukti efektif
utk terapi gagal jantung

-bloker Dosis awal Peningkatan dosis Dosis target Periode titrasi

(mg/hari)

Bisoprolol 1.25 mg od 2.5; 3.75; 5; 7.5; 10 10 mg od Minggu-bulan

Metoprolol suksinat CR 12.5/25 mg od 25; 50; 100; 200 200 mg od Minggu-bulan

Karvedilol 3.125 mg/bid 6.25; 12.5; 25; 50 25 mg bid Minggu-bulan

23
 Diuretik
• Diuretics relieve pulmonary • Diuretics may also decrease afterload by
congestion & peripheral edema. reducing plasma volume, thereby
decreasing blood pressure.
• These agents are also useful in
reducing the symptoms of volume • Loop diuretics are the most commonly used
overload, including orthopnea and diuretics in HF.
paroxysmal nocturnal dyspnea. • These agents are used for patients who
require extensive diuresis and those with
• Diuretics decrease plasma volume
renal insufficiency.
and, subsequently, decrease venous
return to the heart (preload). • As diuretics have not been shown to
improve survival in HF, they should only be
• This decreases cardiac workload and used to treat signs and symptoms of
oxygen demand. volume excess.
24
 Diuretik

• Obat utama gagal jantung akut disertai

kelebihan (overload) cairan  kongesti • Penggunaan diuretik tidak
paru atau edema perifer mengurangi mortalitas pd gagal
• Menghilangkan sesak napas & me↑ jantung (kecuali spironolakton) 
kemampuan aktivitas fisik Pemberian selalu dlm kombinasi dgn
• Mengurangi retensi air & garam penghambat ACE
mengurangi vol. cairan ekstra sel, alir • Tidak boleh diberikan pd gagal
balik vena, tekanan pengisian ventrikel jantung asimtomatik maupun yg tdk
(preload)  edema perifer & kongesti ada overload cairan
paru  berkurang/hilang, sedangkan
curah jantung tidak berkurang (pada fase • Tidak boleh berlebihan tetapi dlm
plateau kurva frank-starling)  diuretik dosis minimal utk mempertahankan
diberikan sampai terjadi diuresis yg cukup euvolemia
utk mencapai euvolemia &
mempertahankannya 25
Diuretik
Tiazid

• Pengobatan gagal jantung tidak pernah diberikan

sendiri (efek diuresi lemah), tetapi dlm kombinasi dgn
diuretik kuat  efek sinergistik
• Tidak digunakan :
• laju filtrasi glomerulus<30mL/menit (tidak efektif), kecuali
diberikan bersama diuretik kuat

26
 Diuretik
Diuretik hemat kalium

• Triamteren, amilorid
• Diuretik lemah  tidak efektif utk kurangi volume
• KEGUNAAN: mengurangi K atau Mg oleh ginjal & atau memperkuat respons
diuresis terhadap obat lain.
• Hanya digunakan jika :
• hipokalemia menetap setelah awal terapi dgn penghambat ACE & diuretik
• Dosis pemberian diuretik hemat kalium dosis rendah selama 1 minggu
• Ukur kadar K & kreatinin serum setelah 5-7 hari sampai kadar K stabil, selanjutnya
setiap 3-6 bulan
27 27
 Dosis & efek samping diuretik oral
Dosis awal Dosis maksimal sehari Lama kerja Efek samping

Diuretik kuat
Furosemid 20-40 mg od/bid 600 mg 6-8 jam Hipokalemia,
hipomagnesemia,
hiponatremi

Bumetanid 0,5-1 mg od/bid 10 mg 4-6 jam Hiperurikemia,

intoleransi glukoas

Torasemid 10-20 mg od 200 mg 12-16 jam Gangguan asam basa

28
 Dosis & efek samping diuretik oral
Dosis awal Dosis maksimal Lama kerja Efek samping utama
sehari

TIAZID
HCT 25 mg od/bid 200 mg 6-12 jam Hipokalemia,
hipomagnesemia,
Klortalidon 12,5-25 mg od 100 mg 24-72 jam hiponatremi

Indapamid 2,5 mg od 5 mg 36 jam Gangguan asam basa

Diuretik hemat
kalium

Amilorid 2,5 mg od 20 mg 24 jam Hiperkalemia, rash

Triamteren 25 mg bid 100 mg 7-9 jam Hiperkalemia
29
 Vaso & Venodilators
• Dilation of venous blood vessels leads to a • A fixed-dose combination of these
decrease in cardiac preload by increasing agents has been shown to improve
venous capacitance. symptoms and survival in black
• Nitrates are commonly used venous dila- tors patients with HFrEF on standard HF
to reduce preload for patients with chronic treatment (β-blocker plus ACE
HF. inhibitor or ARB).
• Arterial dilators, such as hydralazine reduce
systemic arteriolar resistance and decrease • Headache, hypoten- sion, and
afterload. tachycardia are common adverse
• If the patient is intolerant of ACE inhibitors or effects with this combination.
β-blockers, or if additional vasodilator • Rarely, hydralazine has been
response is required, a combination of associated with drug-induced lupus.
hydralazine and isosorbide dinitrate may be
used. 30
Vasodilator lain
• Vasodilator lain & penghambat ACE & antagonis AII yg digunakan utk
pengobatan gagal jantung :
a) Hidralazin-isosorbid dinitrat
b) Na nitroprusid I.V
c) Nitrogliserin I.V
d) Nesiritid I.V

31
Hidralazin-isosorbid dinitrat
• Terbukti dpt mengurangi mortalitas pd psn gagal jantung akibat
disfungsi sistolik
• Psn gagal jantung sistolik yg tdk dpt mentoleransi penghambat ACE &
antagonis AII  mengurangi mortalitas & morbiditas & memperbaiki
kualitas hidup
• Meruapakan vasodilator arteri sehingga menurunkan afterload,
sedangkan isosorbid dinitrat merupakan venodilator sehingga
menurunkan preload jantung

32
NA nitroprusid I.V
• Merupakan prodrug dari nitric oxide (NO)
• Suatu prodrug kuat
• Kerja di arteri & vena  menurunkan afterload maupun preload
jantung
• Mula kerja cepat (2-5 menit) cepat dimetabolisme membentuk NO
yg aktif
• Masa kerja singkat  dosis dpt dititrasi cepat utk capai efek
hemodinamik yg diinginkan
• Atasi gagal jantung  IGD

33
Nitrogliserin I.V
• Prodrug dari NO
• Pada kecepatan invus yg rendah  mendilatasi vena↓preload
jantung
• Digunakan pd gagal jantung kiri akibat iskemia miokard akut, gagal
jantung kiri noniskemik yg memerlukan penurunan preload dgn cepat,
pasien dgn overload cairan yg asimtomatik & belum capai diuresis yg
cukup
• Pada kecepatan infus yg tinggi  mendilatasi arteri  ↓afterload
jantung
• ES : sakit kepala, jika tjd toleransi dpt diatasi dgn me↑dosis
34
Nesiritid I.V
• Rekombinan dari peptida • Mekanisme kerja :
natriuretik otak (BNP) manusia • Peningkatan siklik GMP 
• Indikasi : gagal jantung akut dgn dilatasi vena & arteri
sesak napas saat istirahat atau • Pd gagal jantung, nesiritid
dgn aktivitas minimal mengantagonis efek angiotensin
• Infus selama 24-48 jam & norepinefrin dgn
menurunkan tek.kapiler paru & menimbulkan vasodilatasi,
mengurangi sesak napas natriuresis, diuresis

35
Glikosida jantung
• Efek digosksin pada pengobatan gagal jantung :
a. Inotropik positif
b. Kronotropik negatif (mengurangi frekuensi denyut
ventrikel pd takikardi atau fibrilasi atrium
c. Mengurangi aktivitas saraf simpatis

36
 Obat-obat Inotropic

• All positive inotropes in HFrEF that

• Positive inotropic agents enhance increase intracellular calcium
cardiac contractility and, thus, concentration have been associated
increase cardiac output. with reduced survival, especially in
• Although these drugs act by different patients with HFrEF due to coronary
artery disease.
mecha- nisms, the inotropic action is
the result of an increased • For this reason, these agents, with
cytoplasmic calcium concentration the exception of digoxin, are only
that enhances the contractility of used for a short period mainly in the
cardiac muscle. inpatient setting.
37
 Mekanisme inotropik positif

• Digoksin menghambat pompa Na-K-ATPase pd membran sel otot jantung 

me↑kadar Na+ intrasel  berkurangnya pertukaran Na+ - Ca + + selama
repolarisasi & relaksasi otot jantung  Ca + + tertahan dlm sel , kadar Ca + +
intrasel me↑, ambilan Ca + + ke dlm retikulum sarkoplasmik (SR) me↑
• Ca + + yg tersedia dlm SR utk dilepaskan ke dlm sitosol utk kontraksi me↑ 
kontraktilitas sel otot jantung me↑

38
 Therapeutic uses:
• Digoxin therapy is indicated in patients with severe
HFrEF after initiation of ACE inhibitor, β-blocker, and
Indikasi diuretic therapy.
1. Pasien gagal jantung dgn • A low serum drug concentration of digoxin (0.5 to 0.8
fibrilasi atrium ng/ mL) is beneficial in HFrEF.
• At this level, patients may see a reduction in HF
2. Pasien gagal jantung dgn ritme admissions, along with improved survival.
sinus yg masih simtomatik, • At higher serum drug concentrations, admissions are
terutama yg disertai takikardia, prevented, but mortality likely increases.
meskipun telah mendapat • Digoxin is not indicated in patients with diastolic or
terapi maksimal right- sided HF unless the patient has concomitant
atrial fibrillation or flutter.
• Patients with mild to moderate HF often respond to
treatment with ACE inhibitors, β-blockers,
aldosterone antagonists, direct vaso- and
venodilators, and diuretics and may not require
digoxin. 40
Bioavailibilitas
• Digoksin tablet ± 70-80%
• Bakteri eubakterium lentum memecah digoksin  metabolit tidak
aktifpe↑dosis (standar dosis tdk efektif) pd ± 10% populasi
• T ½ 36-48 jam
• Kadar mantap stlh 1 minggu
• Dieliminasi melalui ginjal, memanjang pd gangguan fungsi ginjal (sp
3,5-5 hari pd ggn fungsi ginjal lanjut)
• Vd 4-7 L/kg, akumulasi obat terutama di otot skelet, dosis tdk perlu
diganti stlh hemodialisis
• Klirens ↓pd usia lanjut  penyesuaian dosis
41
Interaksi penting
a) Kuinidin, verapamil,amiodaron  hambat • Diuretik kuat, furosemid 
P-glikoprotein (P-gp), yakni transporter di
usus halus&tubulus ginjal ↑absorpsi & hipokalemia  me↑toksisitas
pe↓sekresi digoksin  kadar plasma digoksin
digoksin ↑ 70-100%
b) Rifampisin menginduksi transporter P-gp di
• -bloker, verapamil, diltiazem :
usus pe↓kadar plasma digoksin aditif dgn digoksin dlm
c) Aminoglikosida, siklosporin, amfoterisin B memperlambat konduksi
 gangguan fungsi ginjaleksresi digoksin AV&mengurangi efek inotropik
melalui ginjal terganggu ↑kadar plasma
digoksin digoksin
d) Kolestiramin, kaolin pektin, antasida
mengabsorpsi digoksin absorpsi digoksin
me↓

42
Efek Toksik
a) Efek proaritmik, yakni : 1) penurunan potensial istirahat (akibat
hambatan pompa Na)  afterpotential yg mencapai ambang
rangsang & pe↓konduksi AV; 2) pe↑ automatisitas
b) Efek samping GIT : anoreksia, mual, muntah, nyeri lambung
c) Efek samping visual : penglihatan berwarna kuning
d) Lain –lain : delirium, rasa lelah, malaise, bingung, mimpi buruk

43
Kontraindikasi & Dosis

Kontraindikasi Dosis
• Bradikardia • 0,125-0,25 mg /hari jika fungsi
• Blok AV derajat 2 dan 3 ginjal normal
• Sindroma sick sinus • Pada lansia : 0,0625-0,125mg,
kadang-kadang 0,25 mg
• Sindroma wolff-prakinsin-white
• Sediaan : tablet 0,25mg
• Kardiomiopati
• Obstruksi hipertrofik
• Hipokalemia
44
• Digitalis glycosides
• The cardiac glycosides are often called digitalis or digitalis glyco- sides,
because most of the drugs come from the digitalis (foxglove) plant.
• They are a group of chemically similar compounds that can increase the
contractility of the heart muscle and, therefore, are used in treating HF.
• The digitalis glycosides have a low therapeutic index, with only a small
difference between a therapeutic dose and doses that are toxic or even
fatal.
• The most widely used agent is digoxin. Digitoxin is seldom used due to
its considerable duration of action.
45
 Mekanisme kerja
• Regulation of cytosolic calcium concentration: By inhibit- ing the Na+/K+-adenosine
triphosphatase (ATPase) enzyme, digoxin reduces the ability of the myocyte to actively
pump Na+ from the cell.
• This decreases the Na+ con- centration gradient and, consequently, the ability of the
Na+/ Ca2+-exchanger to move calcium out of the cell. Further, the higher cellular Na+ is
exchanged for extracellular Ca2+ by the Na+/Ca2+-exchanger, increasing intracellular
Ca2+.
• A small but physiologically important increase occurs in free Ca2+ that is available at the
next contraction cycle of the cardiac muscle, thereby increasing cardiac contractility.
• When Na+/K+-ATPase is markedly inhibited by digoxin, the resting membrane potential
may increase (−70 mV instead of −90 mV), which makes the membrane more excitable,
increasing the risk of arrhythmias (toxicity).

46
Mekanisme Kerja Digoxin

47
 Mekanisme kerja

• Increased contractility of the cardiac • Neurohormonal inhibition:

muscle: Digoxin increases the force Although the exact mechanism of
of cardiac contraction, causing car- this effect has not been elucidated,
diac output to more closely low-dose digoxin inhibits
resemble that of the normal heart. sympathetic activation with minimal
• Vagal tone is also enhanced, so both effects on contractility.
heart rate and myocardial oxygen • This effect is the reason a lower serum
demand decrease. drug concentration is tar- geted in
HFrEF.
• Digoxin slows conduction velocity
through the AV node, making it
useful for atrial fibrillation.
48
Pharmacokinetics:
• Digoxin is available in oral and injectable formulations.
• It has a large volume of distribution, because it accumulates in
muscle.
• The dosage is based on lean body weight.
• In acute situations such as symptomatic atrial fibrillation, a loading
dose regimen is used.
• Digoxin has a long half-life of 30 to 40 hours.
• It is mainly eliminated intact by the kidney, requiring dose
adjustment in renal dysfunction

49
Adverse effects: • Severe toxicity resulting in ventricular
• At low serum drug concentrations, digoxin is tachycardia may require administration of
fairly well tolerated. antiarrhythmic drugs and the use of
• However, it has a very narrow therapeutic index, antibodies to digoxin (digoxin immune
and digoxin toxicity is one of the most common
adverse drug reactions leading to hospitalization. Fab), which bind and inactivate the drug.
• Anorexia, nausea, and vomiting may be initial • With the use of a lower serum drug
indicators of toxicity. concentration in HFrEF, toxic levels are
• Patients may also experience blurred vision, infrequent.
yellowish vision (xanthopsia), and various • Digoxin is a substrate of P-gp, and inhibi-
cardiac arrhythmias.
tors of P-gp, such as clarithromycin,
• Toxicity can often be managed by discontinuing verapamil, and amiodarone, can
digoxin, determining serum potassium levels,
and, if indicated, replenishing potassium.
significantly increase digoxin levels,
necessitating a reduced dose of digoxin.
• Decreased levels of serum potassium
(hypokalemia) predispose a patient to digoxin • Digoxin should also be used with caution
toxicity, since digoxin normally competes with with other drugs that slow AV conduction,
potassium for the same binding site on the such as β-blockers, verapamil, and
Na+/K+-ATPase pump. diltiazem 50
Ventricular function curves in the normal heart, in heart failure (HF),
and in HF treated with digoxin.

51
Inotropik lain -  adrenergic agonist
Dopamin & dobutamin I.V
Penghambat fosfodiesterase I.V

52
• β-Adrenergic agonists, such as dobutamine [doe-BYOO-ta-meen] and
dopamine [DOH-puh-meen], improve cardiac performance by causing
positive inotropic effects and vasodilation. Dobutamine is the most
commonly used inotropic agent other than digoxin. β-Adrenergic
agonists lead to an increase in intracellular cyclic adenosine
monophosphate (cAMP), which results in the activation of protein
kinase. Protein kinase then phosphorylates slow calcium channels,
thereby increasing entry of calcium ions into the myocardial cells and
enhancing contraction (Figure 19.10). Both drugs must be given by
intravenous infusion and are primarily used in the short-term treat-
ment of acute HF in the hospital setting.
53
Sites of action by β-adrenergic agonists on heart muscle. AMP = adenosine monophosphate; ATP =54
adenosine triphosphate; cAMP = cyclic adenosine monophosphate; P = phosphate
 Dopamin & Dobutamin
Dopamin Dobutamin
•  agonis terpilih utk psn gagal jantung dgn
disfungsi sistolik
• Inotropik yang sering • Campuran rasemik menstimulasi reseptor 1 & 2
digunakan  menunjang • Enansiomer (-)  suatu  agonis
sirkulasi dlm jangka pendek • Pada kecepatan infus  efek inotropik (+) pd
pd gagal jantung yg parah manusia  efek 1 dimiokard dominan ↑curah
jantung dgn sedikit ↑denyut jantung
• Bekerja melalui stimulasi
• Pd pembuluh darah efek  agonis
reseptor dopamin D1 & (vasokonstriksi) dari enansiomer (-) diantagonisasi
reseptor  adrenergik di sel oelh efek 2 agonis (vasodilatasi) dari rasemat
resistensi sistemik sedikit menurun
otot jantung
• Dobutamin tdk menstimulasi reseptor dopamin
• Penggunaan terbatas  psn • Dosis awal 2-3 g/kg/mnt  ditingkatkan sampai
dgn kegagalan sirkulasi efek hemodinamik yg diinginkan
kardiogenik • ES : takikakrdi berlebihan & aritmia  pe↓ dosis
• Psn yg dpt  bloker , respon awal terhadap
dibutamin mgkn lebih kecil
• Penggunaan jangka panajng dpt timbulkan
toleransi  substitusi dgn obt alternatif  55
Penghambat fosfodiesterase
• Inamrinon & milrinon  penghambatan fosfodiesterase kelas III
(PDE3)  penunjang sirkulasi jangka pendek pd gagal jantung yg
parah
• Penggunaan jangka panjang me↑mortalitas (mempercepat kematian)
• Indikasi : penggunaan jangka pendek pd gagal jantung tahap akhir dgn
gejala-gejala refrakter terhadap obat-obat lain

56
 Anjuran – Strategi pengobatan
• Experts have classified HF into four • The dosage is gradually titrated to that
stages, from least severe to most which is maximally tolerated and/or
produces optimal cardiac output.
severe. Note that as the disease
progresses, polytherapy is initiated. • Historically, β-blockers were added after
optimization of ACE inhibitor or ARB therapy
• In patients with overt HF, loop diuret- • patients newly diagnosed with HFrEF are
ics are often introduced first for relief initiated on both low doses of an ACE
of signs or symptoms of volume inhibitor and β-blocker after initial
overload, such as dyspnea and stabilization.
peripheral edema. • These agents are slowly titrated to optimal
levels to increase tolerability.
• ACE inhibitors or ARBs (if ACE • Digoxin, aldosterone antagonists, and fixed-
inhibitors are not tolerated) are dose hydralazine and isosorbide dinitrate are
added after the optimization of initiated in patients who continue to have HF
diuretic therapy. symptoms despite optimal doses of an ACE
inhibitor and β-blocker. 57
 Treatment options for various stages of HF. ACE = angiotensin-converting enzyme; ARBs =
angiotensin receptor blockers; FDC = fixed dose combination; HYD = hydralazine; ISDN =
isosorbide dinitrate. Stage D (refractory symptoms requiring special interventions) is not shown.
58
Sukses selalu

59