Agen Inotropik

Agen inotropik
• Glikoside Jantung (Digitalis)
• Simpatimometik (Dopamin, Dobutamine, NE)
• Inhibitor Fosfodiasterase (Milrinone)
 Pendahuluan
• Agen inotropik positif telah digunakan untuk
mengobati pasien gagal jantung sejak tahun 1775.
• Kinerja obat-obatan inotropik sebagai terapi yang
meningkatkan kinerja kontraktil miokard yang
tidak tergantung dari perubahan heart rate dan
loading condition
• Agen inotropik yang banyak digunakan adalah :
digoxin, dopamine, dobutamine, milrinone, dan
norepinefrine
Figure 1. Simplified schematic of postulated intracellular actions of β-adrenergic agonists. β-
Receptor stimulation, through a stimulatory Gs-GTP unit, activates the adenyl cyclase
system, which results in increased concentrations of cAMP.

Christopher B. Overgaard, and Vladimír Džavík

Circulation. 2008;118:1047-1056

Copyright © American Heart Association, Inc. All rights reserved.

 Digoxin
• Digoxin meningkatkan hemodinamik tanpa berefek pada
tekanan darah atau denyut nadi  tidak meningkatkan
kebutuhan oksigen miokard dann tidak mengurangi perfusi
koroner
• Tidak merusak fungsi ginjal
• Digoxin di ekskresi di ginjal sehingga tidak direkomendasikan
pada pasien dengan gangguan fungsi ginjal
• Tersedia dalam bentuk oral dan intravena
• Meningkatkan hemodinamik saat istirahat dan selama
latihan.
• Digoxin berperan dengan cara menghambat sarkolema
Na+/K+ ATPase pump  menghambat pengangkutan
natrium dari intraselluler ke ekstraseluler  berkurangnya
Na+ dalam transmembran  aktifitas pertukaran
na+/Ca2+ berkurang  kadar ca2+ di intraseluler
meningkat  muncul efek inotropik dan aritmogenik
• Dosis optimal digoxin < 1,0 ng/ml (0,5-0,9 ng/ml)
• Angka mortalitas penggunaan digoxin pada wanita dengan
gagal jantung sistolik lebih besar di banding pria, karenan
cenderung berat badan lebih rendah.
Dopamin, Dobutamin,
Norepinefrin
 Figure 3. A, Endogenous catecholamine synthesis pathway.

Christopher B. Overgaard, and Vladimír Džavík

Circulation. 2008;118:1047-1056

Copyright © American Heart Association, Inc. All rights reserved.

 Dopamin
• Dopamine merupakan prekursor norepinefrin dalam
jalur sintetis katekolamin
• Dopamine berperan sebagai dopaminergik dan
adrenergik
• IV dopamine sudah digunakan untuk pengobatan syok
sepsis dan cardiogenik sejak 1970an
• Pada dosis rendah (<3µg/kg/min) dopamin
mengaktifkan reseptor dopaminergik (D1) 
vasodilatasi vaskular termasuk di arteri koroner dan
arteri renal
• Pada dosis medium (3-10 µg/kg/min) dopamin
mengaktifkan reseptor b-adrenergik  menigkatkan
inotropi dan denyut jantung serta memicu pelepasan dan
menghambat reuptake norepinefrin pada presinaps saraf
terminal simpatis.
• Pada dosis tinggi (10-20µg/kg/min) dopamine bertindak
sebagai agonis a-adrenergik  vasokontriksi perifer
• Dopamin di metabolisme di hepar, ginjal, dan plasma oleh
monoamin oxidase dan cathecol-o-methyl transferase 
NE (aktif)
• Ekskresi 80% di urine
 Dobutamine
• Dikenal sejak tahun 1970an, berefek agonis
secara direk pada reseptor adrenergik b1 dan b2
tanpa adanya vasokontriktor dan sedikit takikardi
• Lebih menguntungkan di banding dopamin 
tidak meningkatkan sinyal simpatis norepinefrin
atau vasokonstriksi periferal.
• Dobutamine menaikkan TD dengan cara
meningkatkan cardiac output
• Efek samping : eosinopfilia
• Dosis : 0,5-1µg/kg/min initial infus iv  2-20µg/kg/min.
• Onset absorpsi 1-10 menit dengan durasi 10 menit
• Time to peak effect 15 min
• Dobutamin dimetabolisme dalam jaringan dan hepar
oleh catchol-o-methyl transferase  3-0-methylated
dobutamine (inactive)
• Half-life 2 menit
• Clearance 90ml/kg/min
• Dobutamin di ekskresikan di urine
• Pada dosis > 15 µg/kg/min dapat terjadi takikardi,
iskemik miokard, dan aritmia selama pemberian infus.
• Short-term infusion untuk 72 jam secara selektif
meningkatkan fungsi endotel vascular selama 2 minggu
• Long term infusion 7-52 hari (durasi median 14 hari)
dengan dosis rata-rata 9µg/kg/min dapat
meningkatkan rate mortality 6 bulan lebih cepat
dibanding dengan vasodilator (data observasional)
• Long term infusion masih digunakan dalam indikasi
heart replacement therapy dan terapi paliatif
 Norepinefrin
• Katekolamin endogen yang di sintesis, disimpan, dan dilepaskan
dari neuron simpatis.
• NE memiliki reseptor agonis a- dan b- adrenergik termasuk
peningkatan kronotropi, inotropi, dan vasokontriksi perifer
• Pemberian NE dilakukan via CVC (central venous catheter) karena
berpotensi menyebabkan nekrosis kulit dan pengelupasan jaringan
• Dosis infus 0,2-1 µg/kg/min
• Dopamin dosis tinggi (>3µg/kg/min) ekuivalen efek dan efek
samping nya dengan dosis normal NE
• Dimetabolisme oleh MAO dan cathecol-o-methyltransferase 
normetanephrine, vanillylmandelic acid (inaktif)
Agen inotropik non adrenergik
(Inhibitor Phospodiasterase)
 Figure 4. Basic mechanism of action of PDIs. PDIs lead to increased intracellular
concentration of cAMP, which increases contractility in the myocardium and leads to
vasodilation in vascular smooth muscle.

Christopher B. Overgaard, and Vladimír Džavík

Circulation. 2008;118:1047-1056

Copyright © American Heart Association, Inc. All rights reserved.

 Milrinone
• Diperkenalkan pada awal tahun 1990 untuk
perawatan gagal jantung sistolik parah
• Milrinon merupakan bipyridine, non
katekolamin, agen inotropik positi dan
vasodilator perifer yang di guunakan secara IV
• Milrinon menghambat PDE -3 enzim yang
merusak cAMP  ca2+ intraseluler dapat
termodulasi  ca2+ masuk ke miosit jantung 
kontraktil miokard meningkat
• Milrinon dapat menurun kan tekanan arteri pulmonaris
via mekanisme vasodilator sehingga dapat
memperbaiki fungsi ventrikel kanan
• Milrinon dan dobutamin sama-sama memicu
peningkatan cardiac output dan penurunan filling
pressure. Tapi milrinon lebih banyak menurunkan LV
filling presure dibanding dobutamin.
• Milrinon memicu hipotensi (khususnya pada pasien
dengan low filling presure), dan aritmia
• KI : pasien dengan kerusakan fungsi ginjal
• Dosis infus awal 0,125 µg/kg/min
• Maintenance :1,13 mg/kg/hari
• Onset absorpsi 5-15 menit (iv) dengan durasi
3-5 hari.
• Dimetabolisme di hepar 12% via glukoronidasi
 milrinone o-glucoronide
• Eksresi di urin 95%, half life 2,5 hari
• Clearance 2,3 mL/kg/min
• Berdasarkan OPTIME-CHF (Outcomes of Prospective
Trial of Intravenous Milrinone for Exacerbations of
Chronic Heart failure) tidak ada rekomendasi untuk
menggunakan milrinon IV sebagai tambahan terapi
standar untuk CHF eksaserbasi.
• Milrinone baik digunakan pada pasien gagal jantung
akut dekompensata, pasien denganhipertensi
pulmo atau pasien yang sedang konsumsi obat b-
adrenergik blocker
 Antiplatelet
• Antiplatelet agents (so called because they inhibit platelet
aggregation) have a role in the prevention of coronary
thrombosis, MI, and cardiac death.
• Antiplatelet agents are not expected to prevent all forms
of thrombotic events.
• Thrombi occurring in arteries are rich in platelets, so
antiplatelet agents are effective. In obstructed arteries,
with low flow, the thrombus consists mainly of red cells
within a fibrin mesh and very few platelets. This situation
is similar to venous thrombosis, in which platelets are not
predominant
 Antiplatelet Therapy:
Targets
Clopidogrel bisulfate Dipyridamol
Ticlopidine e
hydrochloride
Phosphodiesterase
Prasugrel hydrochloride
AD
Ticagrelor P
AD
Gp 2b/3a Inhibitors P
Collagen
Activation Thrombi
n TXA2
CO
X
TXA
Aspiri 2

ADP=Adenosine diphosphate, COX=Cyclooxygenase, TXA2=Thromboxane A2

Source: Schafer AI. Antiplatelet Therapy. Am J Med 1996;101:199–
209
 Aspirin
• Acetylsalicylic acid (aspirin) irreversibly
acetylates cyclooxygenase and activity is not
restored until new platelets are formed
• By inhibiting COX-1, aspirin interferes with the
synthesis of prothrombotic TXA2, important in
the platelet activation cycle
 Membrane Phospholipids

Arachadonic Acid

COX- Aspiri
1 n

Prostaglandin H2

Thromboxane A2 Prostacyclin
 Platelet Aggregation  Platelet Aggregation
Vasoconstriction Vasodilation
 ADP /
ATP
Receptor
Antagonist P2Y
P2X1 P2Y12
1

Cation influx Calcium mobilization

Ca2+ Ca2+ cAM

P

No effect on Fibrinogen receptor

Platelet shape change
fibrinogen activation
Transient aggregation
receptor Thromboxane A2
generation
Sustained Aggregation Response
Sources:
Savi P et al. Biochem Biophys Res Commun 2001; 283:379–383
Ferguson JJ. The Physiology of Normal Platelet Function. In: Ferguson JJ,
Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice.
London: Martin Dunitz; 2000: pp.15–35
 Acetylsalicylic Ticlopidine Clopidogrel Prasugrel Ticagrelor
acid (ASA) hydrochloride bisulfate
hydrochloride
Class Salicylate P2Y12 Receptor P2Y12 Receptor P2Y12 Receptor P2Y12 Receptor
Antagonist Antagonist Antagonist Antagonist

Formulation Active Drug Active Drug Pro-Drug Pro-Drug Active Drug

Maintenance 75-325 mg 250 mg BID 75 mg daily 10 mg daily 90 mg BID

Dose daily*
Reversible No No No No Yes

*81 mg is the low dose aspirin option in the United States

Sources:
1 Pearson TA, et al. Circulation, 2002;106:388-391
2Mosca L, et al. Circulation, 2007;115:1481-1501

3 Smith SC Jr. et al. JACC 2011;58:2432-2446

4http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/19-979S018_Ticlid_prntlbl.pd

f 5http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020839s042lbl.pdf 6
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022307s001lbl.pdf 7
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardiova
scularandRenalDrugsAdvisoryCommittee/UCM221383.pdf
 anticoagulant
• As a group, the warfarin-like oral
anticoagulants inactivate vitamin K in the
hepatic microsomes, thereby interfering with
the formation of vitamin K–dependent clotting
factors such as prothrombin. In addition,
factor X may be reduced.
Group Health. Venous Thromboembolism (VTE) Diagnosis & Treatment Guideline. 2011
Group Health. Venous Thromboembolism (VTE) Diagnosis & Treatment Guideline. 2011
Group Health. Venous Thromboembolism (VTE) Diagnosis & Treatment Guideline. 2011
2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism
 Anti Coagulation
• Parenteral Anticoagulantion
– UFH IV
indicates :serious renal impairment (creatinine clearance <30
mL/min), severe obesity
The dosing of UFH is adjusted, based on the activated partial
thromboplastin time
– LMWH or Fondaparinux Subcutaneous
- preferred over UFH for initial anticoagulation in PE  lower risk
of inducing major bleeding and heparin-induced
thrombocytopenia (HIT)
- the target doses range is 0.6–1.0 IU/ mL for twice-daily adm and
1.0–2.0 IU/mL for once-daily adm
- fondaparinux contraindicated : severe renal insufficiency
(creatinine clearance <30 mL/min)  accumulate and increase
the risk of haemorrhage.2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism
• Oral Anticoagulation
– Vit K Antagonists
• VKAs have been the ‘gold standard’ in oral anticoagulation
– Warfarin
• started at a dose of 10 mg in younger otherwise healthy outpatients, and at a
dose of 5 mg in older patients and in those who are hospitalized.
– New oral Coagulation
As an alternative to the combination of parenteral anticoagulation
with a VKA
- rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once
daily)
- apixaban (10 mg twice daily for 7 days, followed by 5 mg twice daily
- dabigatran (150 mg twice daily, or 110 mg twice daily for patients
>80 years of age or those under concomitant verapamil treatment
- rivaroxaban, apixaban, dabigatran, edoxaban are not recommended
in patients with severe renal impairment

2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism
2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism