Farmakologi Obat Kardiovaskuler I

Materi:
1. Obat pada angina pektoris
2. Obat pada Sindroma Koroner Akut (SKA):
antiplatelet, antikoagulan, trombolitik, statin

dr. Mochamad Ali Sobirin, PhD, SpJP

FK Unwahas 2019
 Angina Pectoris
Angina Pectoris adalah sensasi tidak nyaman pada dada
(strangling in the chest) dan struktur anatomis di sekitarnya
disebabkan oleh iskemik miokard.

Spektrum klinisnya dapat berupa:

1. Angina stabil
Tipe kronik, dipicu oleh aktifitas fisik dan emosi, berkurang
dengan istirahat (Angina of effort)
2. Angina tidak stabil
Angina stabil yang frekuensi dan durasi iskemiknya meningkat
dengan aktifitas lebih ringan bahkan saat istirahat,
3. Angina spastik (Variant, Prinzmetal)
Angina yang disebabkan oleh spasmus arteri koronaria.
 Patofisiologi

Normal Angina stabil

Endothelial cell
Plaque

Patent lumen Lumen narrowed )

Lumen Endothelial function N Vasoconstriction +
Lumen
Lumen

Angina tidak stabil Angina spastik

Platelets
Thrombus No plaque
Lumen Intense vasospasm
Lumen Plaque rupture
Platelet aggregation
Thrombus +
Vasoconstriction +
 Prinsip Pengobatan
Dept. of Pharmacology and
Therapeutics Angina Pectoris
Myocardial oxygen supply: Myocardial oxygen demand:

O2 content Wall stress

Coronary blood flow Heart rate

• Coronary perfusion pressure

• Coronary vascular resistance Contractility

meningkatkan penyediaan dan menurunkan kebutuhan oksigen

pada otot jantung
 Pengobatan Angina Pectoris
Dept. of Pharmacology and
Therapeutics

Untuk mencegah kekambuhan gejala iskemik:

1. Nitrat
2. Kalsium antagonis (CCB)
3. Penyekat Beta (Beta bloker)
 Farmakodinamik Nitrat (1)
Endo Cytoplasm
Isosorbide
dinitrate Sarcolemma
Isosorbide
mononitrate Peroxynitrite
GTP
LIVER Physiologic
dilators 
NO
Cyclic
GMP
Mononitrate
Nitrosothiols
R-ONO2
ONO2 SH Lowers
Nitroglycerin Ca2+
ONO2 NO2
ONO2
ONO2
EXCESS NITRATES VASO-
SH DILATION
• Deplete SH
• Peroxynitrite
Nitrate tolerance Opie (2013)

Effects of nitrates in generating NO and stimulating guanylate

cyclase to cause vasodilation.
 Nitrat (2)
• Mekanisme kerja:
1.Dilatasi vena sistemik
2.Vasodilatasi koroner (epicardial dan arteriole):
• redistribusi arteri kolateral
• kurangi spasme, stenosis termasuk ok exercise

• Tujuan pemakaian obat:

1.Mengurangi serangan akut angina
2.Pencegahan jangka panjang serangan angina

• Agen obat:
1.Nitrogliserin
2.Isosorbid dinitrat
3.Isosorbid mononitrat
 Pharmacokinetics Nitrat (3)
Dept. of Pharmacology and
Therapeutics

1. Nitrogliserin
Sublingual (Tablet atau Spray): onset 1-3 menit, efek
berkurang setelah 15-30 min.
Transdermal:onset 40-60 menit, lama kerja 4-8 jam.
Intravenous: u/ angina tdk stabil dan gagal jantung akut.
2. Isosorbid dinitrat (ISDN)
Sublingual:onset 2-5menit,durasi 1-2jm.
Per oral:onset 20-40menit,durasi 4-6jam.
3. Isosorbid mononitrat
Per oral Waktu paruh > lama dan metabolisme tingkat
pertama < dibanding ISDN.....Bioavaibilitas
 Efek samping
obat:
1. Flushing
2. Sakit kepala
3. Refleks takikardi
4. Hipotensi
 Interaksi obat:
1.PDE 5 inhibitor
(Viagra)
KONTRAINDIKASI!
Cara atasi:
Pemakaian nitrat > 24
jam
2.Hydralazine…..BENE
FICIAL
Toleransi nitrat
berkurang ok hambat
radikal bebas
 Toleransi Nitrat
Adalah berkurangnya efek obat nitrat ketika diberikan dalam
jangka waktu yang lama

 Terjadi pada semua golongan nitrat diduga:

 prolonged nitrat produksi peroksinitrit (hambat
eNOS)
 long-acting nitrates: disfungsi endotel?
 Tergantung dosis
 Hilang apabila menghentikan obat selama 24 jam
 Toleransi dapat dihindari dengan:
- gunakan dosis efektif paling minimal
- setidaknya 10 jam nitrat free interval/hari
 Mekanisme Kerja Beta Bloker

increased
diastolic
heart rate perfusion
after load less exercise
wall O2 vasoconstriction
stress demand O2
heart size supply
more spasm?
contractility collateral
flow
O2 wastage

DEMAND SUPPLY

•Mekanisme Kerja:
Hambat kerja reseptor β (β1 O2 deficit
pada otot jantung, efek lain β2
pada bronkus dan pembuluh anaerobic metabolism (Opie, 2012)
darah).
Penyekat Beta/ Beta Bloker: Farmakokinetik

Opie LH et al. Drugs for the heart, 8th ed, 2013

Penyekat Beta/ Beta Bloker: Farmakodinamik

Efek Samping
Obat:

1. Bradikardi
2. Konstriksi
bronkus
3. Memperburuk
kontrol diabetes
4. Fatique
 Klinis Beta Bloker pada Angina
• All b-blockers are potentially equally effective in angina pectoris

• Non-responder:
(1) underlying severe obstructive coronary artery disease
(2) increase in LV end-diastolic pressure (negative inotropic)

• A major benefit: restricted increase in the HR during exercises

(should not exceed 100 beats/min in patients with angina)

• b-blockers are often combined with nitrate vasodilators and

calcium channel blockers (CCBs)

• b-blockers less recommended for Prinzmetal and cold intolerance

• When b-blockers are suddenly withdrawn, angina may be

exacerbated
Mekanisme Kerja Kalsium Antagonis
± or  heart rate Collateral flow 

 or  afterload Vasodilation 

Wall O2
stress demand O2
supply
± pre-load

± or  contractility DEMAND  SUPPLY 

(variable)

Some O2 deficit 

DHPs
Reflex DEMAND 
adrenergic
Rapid
vasodilation
Opie (2013)
 Kalsium antagonis (1)
Mekanisme Kerja:
Hambat L-type kalsium channel, relaksasi otot polos p.d dan
efek inotropik negatif

1.Dihydropyridines (Nifedipine dan Amlodipine)

Kebutuhan O2 turun karena dilatasi vena dan arteri
Supply O2 naik karena dilatasi arteri koronaria
 Dosis: Nifedipine extended release 30-90 mg 1x/hari

2.Nondihydropyridines (Verapamil dan Diltiazem)

<< Vasodilator dibanding dihydropyridines
 >> HR lowering agents
Fs lain: mendepresi denyut nadi dan kontraktilitas miokard
 Dosis : Diltiazem extended release 120-360 mg 1x/hari.
 Kalsium antagonis (2)
Dept. of Pharmacology and
Therapeutics

• Biasanya diberikan secara per oral dalam bentuk long acting

(formulasi 1x/hari), hindari short acting
• Pemberian secara intravena untuk Diltiazem dan Verapamil
• Efek samping obat:
1. Flushing, sakit kepala
2. Edema perifer
3. Hipotensi
4. Konstipasi (Verapamil)
5. Bradikardi (Waspada pemakaian bersama dengan penyekat
beta)
 Co-terapi pada Angina Pectoris
Dept. of Pharmacology and
Therapeutics

Obat untuk mencegah sindroma akut koroner dan kematian:

1. Anti platelet
2. Statins
3. ACE-Is dan ARBs
Dept. of Pharmacology and
Therapeutics

Obat pada Sindroma Koroner Akut

(SKA)

1. Antiplatelet
2. Antikoagulan
3. Trombolitik (Fibrinolisis)
4. Drugs (ACE-I/ARB, Beta Bloker, MRA, anti-
aritmia, Statin)
 Clinical case: Sindroma koroner akut
3 Jam
SMRS

- Nyeri dada bagian tengah sehabis

sholat subuh di mushola (04.30)
- Dada terasa seperti ditindih barang
berat, durasi > 30 menit, terus
menerus,
- Tidak kurang buat istirahat,
perubahan posisi maupun respirasi
- Dijalarkan ke punggung
- Disertai keringat dingin, berdebar-
debar, muntah; pingsan (-), sesak
nafas (-)
- (07.00) nyeri tidak berkurang,
dibantu mantri dibawa ke UGD
RSDK
Patofisiologi SKA
 Manajemen SKA
STEMI UAP/NSTEMI
Reperfusion Approach All patients Antithrombotic Approach

• Aspirin • General : • Aspirin

• Heparin • Pain control • Heparin
(UFH/LMWH) (morphine) (UFH/LMWH)
• Ticagrelor/ • Oxygen
• Clopidogrel/
Prasugrel/ • Anti ischemic : Prasugrel/
Clopidogrel • β blocker Ticagrelor
• Reperfusion • Nitrates
• +/- Ca blocker
• For high risk
method : patients :
A.Fibrinolytic • Additional : • GP IIb/IIIa
B.Primary PCI • ACE inhibitor
(+GPIIb/IIIa inhibitor
• Statins • Early invasive
inhibitor)
strategy
Aspirin:
Mechanism of Action
Membrane Phospholipids

Arachadonic Acid

COX-1 Aspirin

Prostaglandin H2

Thromboxane A2 Prostacyclin (endhotelial)..recover in hours

 Platelet Aggregation  Platelet Aggregation
Vasoconstriction Vasodilation
 Acetylsalicylic acid (Aspirin) – PK/PD
• Rapid absorption of aspirin (stomach and upper
intestine), peak plasma concentration 15-20 minutes
• The peak inhibitory effect on platelet aggregation in one
hour post-administration
• Aspirin produces the irreversible inhibition of the enzyme
cyclo-oxygenase; causes irreversible inhibition of
platelets for the rest of their lifespan (7 days)
• Major use:
– Secondary prevention of transient ischaemic attack (TIA),
ischaemic stroke and myocardial infarction
– Prevention of ischaemic events in patients with angina pectoris
 Acetylsalicylic acid – major drawbacks

• Risk of gastrointestinal adverse events (ulceration and

bleeding)
• Allergic reactions
• Is not a very effective antithrombotic drug but is
widely used because of its ease of use
• Lack of response in some patients (aspirin resistance)
• The irreversible platelet inhibition
 Aspirin Evidence:

Secondary
Effect of antiplatelet Prevention
treatment* on vascular events**

Category % Odds Reduction

Acute MI
Acute CVA
Prior MI
Prior CVA/TIA
Other high risk
CVD
(e.g. unstable angina, heart failure)
PAD
(e.g. intermittent claudication)
High risk of embolism (e.g. Afib)
Other (e.g. DM)
All trials

0.0 0.5 1.0 1.5 2.0

Antiplatelet better Control better

menurunkan angka reinfark 50% dalam 30hari ;

20% penurunan mortalitas dlm 2 tahun
Source: Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71–86
 P2Y12 Receptor Antagonist:
Mechanism of Action
P2Y12 Receptor ADP / ATP

Antagonist
P2Y1
P2X1 P2Y12

Gq coupled
Cation influx Calcium mobilization Gi2 coupled

Ca2+ Ca2+ cAMP

No effect on Platelet shape change

fibrinogen Fibrinogen receptor activation
Transient aggregation
receptor Thromboxane A2 generation

• The P2Y12 receptor antagonists

selectively bind P2Y12 (ADP receptors) Sustained Aggregation Response
• inhibits ADP-induced activation of the Sources:
Savi P et al. Biochem Biophys Res Commun 2001; 283:379–383
platelet glycoprotein IIb/IIIa-receptor and
prevents platelet aggregation 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
P2Y12 inhibitor: Pharmacokinetics
PY12 inhibitor: Pharmacokinetics
Ticagrelor Evidence:
Secondary Prevention
Platelet Inhibition and Patient Outcomes (PLATO) Study
18,624 patients with a moderate to high risk ACS randomized to clopidogrel (300-600
mg LD and 75 mg MD) or ticagrelor (180 mg LD and 90 mg twice daily MD) for 12
months

12 11.7 HR 0.84, p=0.001

Clopidogrel
9.8
10
CV Death, MI, or

8 Bleeding Events*
Stroke (%)

Ticagrelor C (%) T (%)

6
TIMI major/year 7.9 7.7
4 PLATO major/year 11.6 11.2
2 Life threatening/year 5.8 5.8
Fatal/year 0.3 0.3
0
0 60 120 180 240 300 360
Days after randomization

Ticagrelor reduces ischemic events with no higher rate of bleeding overall

*No statistically significant differences were observed in bleeding rates overall

ACS=Acute coronary syndrome, CV=Cardiovascular, LD=Loading
dose, MD=Maintenance dose
Source: Wallentin L et al. NEJM 2009;361:1045-1057
 ANTIKOAGULAN

•Heparin ( Unfractionated Heparin)

•Low Molecular Weight Heparin
•Fondaparinux
 Intrinsic Pathway Extrinsic Pathway
Blood Vessel Injury Tissue Injury

Tissue Factor
XII XIIa

Thromboplastin
XI XIa

IX IXa VIIa VII

X Xa X

Prothrombin Thrombin
Factors affected
By Heparin Fibrinogen Fribrin monomer

Vit. K dependent Factors Fibrin polymer

XIII
Affected by Oral Anticoagulants
 Heparin (UFH)
Structure
Mucopolysaccharide
Metabolism
Partially in the liver by heparinase to uroheparin, which has
only slight antithrombin activity.
20-50 % is excreted unchanged.
{The heparin polysaccharide chain is degraded in the gastric
acid} administered IV or SC.
Heparin should not be given IM }danger of hematoma
formation{
Antidote:
Protamine sulphate
Use in pregnancy :{does not cross the placenta} safe
3000-30000
Mechanism of action:
•Primarily: interaction with antithrombin III: alters the molecular
configuration of antithrombin III, making it 1,000 to 4,000 times more
potent as an inhibitor of thrombin formation: limits conversion of
fibrinogen to fibrin: prolongs aPTT
•Also inhibits the effects of factor Xa on the coagulation cascade &
limits platelet aggregation.
Half-life:
IV: 1 hr
SC: 3 hrs.
• Hospitalization/ PTT/ bleeding
• Anti-Xa: Anti-thrombin 1:1
 Low Molecular Weight Heparin
• Mekanisme Kerja:
– Primarily by inhibiting factor Xa, which is higher in
the coagulation cascade than antithrombin: LMWH is
more efficient than UFH.
– {the molecular configuration of antithrombin III is not altered
by LMWH} thrombin conversion is minimally inhibited
and aPTT is not appreciably affected.
• Depolimerasi dari UFH standar dengan berat molekul lebih
kecil dari pada UFH (1000-10000 Da.)
• SC injections/ 90% bio-available/predictable
• Anti-Xa: Anti-thrombin 2-4:1
• Use in pregnancy :{does not cross the placenta} safe
UFH

LMWH
 KELEMAHAN UFH
• Bioavailability kurang baik
• Tidak dapat menghambat trombin yang terikat pada
bekuan (clot-bound thrombin)
• Tergantung pada kofaktor AT III
• Efek variabel
• Monitor APTT berkala untuk mendapatkan kadar
terapeutik
• Rebound iskemia setelah penghentian
• Risiko heparin-induced thrombocytopenia (HIT)

Panduan Terapi SKA tanpa ST Elevasi PERKI 2004

 KEUNGGULAN DARI LMWH

• Mengurangi ikatan pada protein pengikat heparin

• Efek yang dapat diprediksi lebih baik
• Tidak memerlukan pengukuran APTT
• Pemakaian subkutan,menghindari kesulitan dalam
pemakaian secara IV
• Berkaitan dengan kejadian perdarahan yang kecil,
namun bukan perdarahan besar
• Stimulasi trombosit kurang dari UFH dan jarang
menimbulkan HIT
• Penghematan biaya perawatan (dari studi ESSENCE)
Fondaparinux: pharmacology
• Synthetic polysaccharide
• Indirect, selective factor Xa inhibitor
• Binds to antithrombin III
 Fondaparinux: pharmacology
• More pharmacologic benefits:
– Binds specifically to antithrombin III and not to irrelevant
plasma proteins
Paolucci, et al. 2002.

– Exhibits no inhibitory effect on platelet aggregation

Messmore, et al. 1989.

– Favorable pharmacokinetic profile after SC administration

• 100% absorption into plasma
• Maximal concentration in 2h
• Relatively long half-life (17h)
• Predictable dose response, independent of age or sex
– Metabolism:
• 100% renal clearance (same as LMWH)
• No studies on renal dose-adjustment
– Thus, GFR < 30mL/min (≈ Cr > 265mmol/L) is a contraindication
 Pharmacologic comparison
Pharmacotherapy 23(6):772-787, 2003

Property UFH LMWH Fondaparinux

Source animal animal synthetic
T1/2 ~3h ~4h (variable) 17-21h
Bioavailability
30% >90% 100%
(SC)
Reticuloendothelial and
Elimination renal renal
renal
Induced HIT* 2-5% 1-2% Not observed
Inter or intra-
+++ ++ +
patient variability
aPTT
Monitoring Plt count nil
Plt count
Reversal Protamine Protamine FFP
 Fondaparinux
Advantages Disadvantages
• SC administration
• Once-daily • Difficult to monitor (no
• Fixed dose aPTT or ACT)
• Predictable response • Long half-life
• No antigenicity
• Catheter thrombosis
during PCI

Simoons ML: J Am Coll Cardiol 2004;43:2183-2190

Yusuf S: N Engl J Med 2066; 354:1464-1476
TEHNIK INJEKSI LMWH SUBKUTAN
 AGEN FIBRINOLITIK

Streptokinase (SK)
Actylase (tPA)
Reteplase (r-PA)
Tenecteplase (TNK-tPA)
 Skema sistem fibrinolitik
Plasminogen Activators
(t-PA, u-PA)

Plasminogen Activator
Inhibitors (PA1, PA2, TAFI)

Plasminogen Plasmin

α2-Antiplasmin
Fibrin
Fibrin degradation
Product
Braunwald, A Textbook of Cardiovascular Medicine. 6th ed
SPESIFISITI FIBRIN BERBAGAI AGEN FIBRINOLITIK
• Streptokinase Rendah
• Actylase (tPA)  Tinggi
• Reteplase(r-PA) Sedang
• Tenecteplase  Sangat tinggi
(TNK-tPA)
CARA PEMBERIAN FIBRINOLITK
• Streptokinase ( Streptase )
1.5 million Unit in 100 ml D5W or 0.9% saline selama
30-60 mnt
• tPA
15 mg IV bolus kemudian 0.75 mg/Kg selama 30
mnt,dilanjutkan 0.5 mg/Kg selama 60 mnt berikutnya
 Streptokinase (SK, Streptase)

• Keuntungan : lebih baik pada anterior MCI, age <75;

lebih murah
• Komplikasi: antigenic, perdarahan intraserebral pada
studi GUSTO 0.6%
• Trials: GISSI-1, ISIS-2 (88)
 Intensity of Statin Therapy

*Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There
might be a biologic basis for a less-than-average response.
†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al).
‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not
recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis.
Robert H. Knopp, M.D. N Engl J Med 1999; 341:498-511
Side Effects Statin
Terima kasih