• Angina Pectoris: simptom tipikal yg berhub dg

iskemia miokard & biasanya disebbkan oleh

penyempitan atheromatous dr arteri koroner.
Simptom ini terdiri dari rasa sesak (nyeri) di dada
(biasanya retrosternal) dan sering menyebar ke
lengan, dipresipitasi oleh exercise & hilang dg
istirahat & nitrat
Penyebb utama angina pektoris: ketdkseimbangan
antara kebutuhan O2 jtg dg jml O2 yg dipasok
ke jantung mll pemblh darah koroner
Ketdkseimbangan antara pengiriman & kebutuhan
O2 miokardium dpt dikoreksi dg
• me pengiriman (me aliran darah koroner)
• me↓ kebutuhan O2 (me↓ kerja jantung)
Nitrat adlh obat lini pertama
Jk tdk efektif dpt ditambah β blocker atau Ca
antagonis
Angina pectoris has three overlapping patterns:
1) effort-induced, stable, classical, or typical angina;
2) unstable angina; and
3) Prinzmetal, variant, vasospastic, or rest angina.
They are caused by varying combinations of increased
myocardial demand and decreased myocardial
perfusion.
A. Effort-induced angina, classic or stable angina.
typical angina pectoris.
characterized by a shortlasting burning, heavy, or
squeezing feeling in the chest.
caused by the reduction of coronary perfusion due to a
fixed obstruction of a coronary artery produced by
atherosclerosis.
Due to the fixed obstruction, the blood supply cannot
increase, and the heart becomes vulnerable to
ischemia whenever there is increased demand, such as
that produced by physical activity, emotional
excitement, or any other cause of increased cardiac
workload.
B. Unstable angina
classified between stable angina and myocardial
infarction.
In unstable angina, chest pains occur with
increased frequency, duration, and intensity
and are precipitated by progressively less
effort.
The symptoms are not relieved by rest or
nitroglycerin.
Prinzmetal, variant, vasospastic or rest-angina
an uncommon pattern of episodic angina that
occurs at rest and is due to coronary artery
spasm.
Symptoms are caused by decreased blood flow
to the heart muscle from the spasm of the
coronary artery.
generally responds promptly to coronary
vasodilators, such as nitroglycerin and
calcium-channel blockers.
Mixed forms of angina
Patients with advanced coronary artery disease
may present with angina episodes during
effort as well as at rest, suggesting the
presence of a fixed obstruction associated
with endothelial dysfunction and vasospastic
disease.
Acute coronary syndrome
Acute coronary syndrome is an emergency, which
commonly results from rupture of an
atherosclerotic plaque and partial or complete
thrombosis of a coronary artery.
disruption of an atherosclerotic lesion typified by a
large lipid pool; numerous inflammatory cells;
and a thin, fibrous cap (soft plaque→activation of
the coagulation cascade and vasoconstriction→
intraluminal thrombosis and vascular occlusion.
• Jk β blocker tdk dpt digunakan, mis pd
pasien asma, Ca antagonis dpt ditambahkan
• Ca antagonis mempunyai aksi pd jantung,
ttp Ca antagonis menghilangkan angina
terutama dg menyebbkan dilatasi arteriolar
perifer dan pe↓ afterload→ t.u berguna
utk terapi spasmus arteri koroner (angina
varian)
• Pd pasien unstable angina, terdpt resiko
yg cukup tinggi utk tjdnya infark
miokard→ selain β blocker, pasien perlu
diterapi jg dg obat antitrombosit &
heparin utk mengurangi agregasi
trombosit & trombosis
• Jk simptom tdk terkontrol,
revaskularisasi sgt dianjurkan dg
coronary bypass graft atau angioplasti
Blood flow in a coronary
artery partially blocked with
atherosclerotic plaques
Treatment of angina in patients with concomitant diseases.
COPD = chronic obstructive pulmonary disease
 Treatment guidelines for
improving symptoms in
patients with stable angina.
 Organic nitrates
For example, isosorbide dinitrate and isosorbide
mononitrate are solids at room temperature,
nitroglycerin is only moderately volatile, and
amyl nitrite is extremely volatile.
cause a rapid reduction in myocardial oxygen
demand, followed by rapid relief of symptoms.
effective in stable and unstable angina as well as
in variant angina pectoris.
 Organic nitrates

• Ester asam nitrat & nitrit yg sederhana dr

polialkohol
• Mulai dr cairan yg luar biasa mdh menguap
(amilnitrit), jg cairan yg ckp mdh menguap
(nitrogliserin) hingga btk padat (isosorbid
dinitrat)
• Tablet nitrogliserin SL konvensional
kehilangan kekuatan bila disimpan pd
permukaan plastik
• Semua agent terapeutik mampu merilis nitric
oxide (NO) dlm jaringan target otot polos
vaskular
 Organic nitrates

A. Mechanism of action
Nitrates inhibit coronary vasoconstriction or spasm,
increasing perfusion of the myocardium and,
thus, relieving vasospastic angina. In addition,
nitrates relax the veins (venodilation), decreasing
preload and myocardial oxygen consumption.

effective in treating effort-induced angina (classic

angina).
Organic nitrates, such as nitroglycerin, which is also known as
glyceryl trinitrate, are thought to relax vascular smooth muscle
by their intracellular conversion to nitrite ions and then to nitric
oxide, which, in turn, activates guanylate cyclase and increases
the cells’ cyclic guanosine monophosphate (cGMP).1 Elevated
cGMP ultimately leads to dephosphorylation of the myosin light
chain, resulting in vascular smooth muscle relaxation
• Mekanisme kerja: metabolisme obat akan
melepaskan ion nitrit (NO2-), dlm sel NO2- akan
diubah mjd nitrik oksida (NO), yg kmdn
mengaktifkan guanilil siklase yg menyebbkan pe
cGMP dlm sel otot polos vaskuler→ defosforilasi
myosin light chain (relaksasi)
• Efektivitas pd terapi angina dihasilkan oleh pe
beban kerja jantung (bekerja pd vena m pre
load & pd arteri me after load) & oleh dilatasi
arteri koroner kolateral
 Organic nitrates

Effects on the cardiovascular system

All of these agents are effective, but they differ in
their onset of action and rate of elimination.
For prompt relief of an ongoing attack of angina
precipitated by exercise or emotional stress,
sublingual (or spray form) nitroglycerin is the
drug of choice.
At therapeutic doses, nitroglycerin has two major
effects.
 Organic nitrates

1. causes dilation of the large veins, resulting in

pooling of blood in the veins. This diminishes
preload (venous return to the heart) and
reduces the work of the heart.
2. nitroglycerin dilates the coronary
vasculature, providing an increased blood
supply to the heart muscle. Nitroglycerin
decreases myocardial oxygen consumption
because of decreased cardiac work.
 Organic nitrates

C. Pharmacokinetics
The time to onset of action varies from 1 minute for
nitroglycerin to more than 1 hour for isosorbide
mononitrate.
Significant first-pass metabolism of nitroglycerin occurs in the
liver. Therefore, it is common to take the drug either
sublingually or via a transdermal patch, thereby avoiding
this route of elimination.
Isosorbide mononitrate owes its improved bioavailability and
long duration of action to its stability against hepatic
breakdown.
Oral isosorbide dinitrate undergoes denitration to two
mononitrates, both of which possess antianginal activity.
Time to peak effect
and duration
of action for some
common organic
nitrate preparations
 Organic nitrates

• Short-acting nitrat. Gliseril trinitrat (SL atau

spray) bekerja selama 30 mnt. Lbh berguna
mencegah serangan dibanding menghentikan
serangan yg sedang berlangsung. Patch
(transdermal) dpt berdurasi hingga 24 jam
• Long-acting nitrat. Isosorbid dinitrat digunakan
scr luas, ttp dimetabolisme dg cepat oleh liver.
Isosorbid mononitrat (metabolit aktif dinitrat)→
dpt menghindari abs yg bervariasi & metab lintas
pertama yg unpredictable
 Organic nitrates
• Bioavailabilitas nitrat organik oral
(nirogliserin & ISD) sgt rendah ( <10-20%)
• Pemberian SL utk menghindari efek lintas-
pertama mencapai kadar darah tx dg cepat
(bbrp mnt), durasi singkat (15-30mnt)
• Amilnitrit tersedia di dlm ampul kaca rapuh
yg terbungkus di dlm suatu kain penutup 
rute penghirupan menghslkan absorbsi yg sg
cpt menghindari efek lintas pertama
hepatis
• Metabolit aktif ISD: 5 mononitrat tersedia
utk penggunaan klinis sbg isosorbid
mononitrat bioavailablitas 100%
• Ekskresi: tu dlm btk turunan glucuronid sbg
bsr mll ginjal
 Organic nitrates
Tolerance
Tolerance to the actions of nitrates develops rapidly. The blood
vessels become desensitized to vasodilation.
Tolerance can be overcome by providing a daily “nitrate-free
interval” to restore sensitivity to the drug.
This interval is typically 10 to 12 hours, usually at night, because
demand on the heart is decreased at that time. Nitroglycerin
patches are worn for 12 hours, then removed for 12 hours.
However, variant angina worsens early in the morning, perhaps
due to circadian catecholamine surges. Therefore, the
nitrate-free interval in these patients should occur in the late
afternoon.
Patients who continue to have angina despite nitrate therapy
may benefit from addition of another class of agent.
 Organic nitrates

• Toleransi dpt tjd & scr klinis penting pd

penggunaan obat long-acting atau sediaan
lepas lambat
• Mis. dosis moderat Isosorbid dinitrat (ISD)
oral 4 kali sehari dpt menybbkan toleransi
berupa hilangnya efek antianginal
• ISD 2 kali sehari (08.00 & 13.00) tdk
menybbkan toleransi, mungkin krn selama
tidur malam sensitivitas jaringan pulih kembali
 Clinical uses of organic nitrates
• Stable angina:
- pencegahan (mis isosorbid mononitrat
atau gliseril trinitrat sublingual segera sblm
beraktivitas)
- Tx (gliseril trinitrat SL)
• Unstable angina: gliseril trinitrat IV
• Chronic heart failure: isosorbid mononitrat
dg hidralazin jk ACE Inh dikontraindikasikan
 Organic nitrates

• Efek samping: dilatasi arterial

menyebbkan nyeri kepala, hipotensi &
pingsan. Refeks takikardi sering tjd ttp
dpt dicegah dg kombinasi dg β-blocker.
Pemberian jk panjang dpt menyebbkan
methemoglobinemia akibat oksidasi Hb
 Organic nitrates

Adverse effects
The most common adverse effect of
nitroglycerin, as well as of the other nitrates, is
headache.
High doses of organic nitrates can also cause
postural hypotension, facial flushing, and
tachycardia.
 β-blockers
↓ the oxygen demands
They suppress the activation of the heart by
blocking β1 receptors,
↓ the work of the heart by decreasing heart
rate, contractility, cardiac output, and blood
pressure.
With β-blockers, the demand for oxygen by the
myocardium is reduced both during exertion and at
rest. Because of these effects, β-blockers are the
drugs of choice to treat effort-induced angina.

The β-blockers reduce the frequency and severity of

angina attacks.

β-Blockers are ineffective against and should not be

used in vasospastic angina. Propranolol is the
prototype for this class of compounds, but it is not
cardioselective.
Thus, other β-blockers, such as metoprolol and
atenolol, are preferred. [Note: All β-blockers are nonselective at
high doses and can inhibit β2 receptors. This is particularly important to remember
in the case of asthmatic patients.]

Agents with intrinsic sympathomimetic activity (for

example, pindolol ) are less effective and should
be avoided in angina.

Similarly, β-blockers without intrinsic

sympathomimetic activity are particularly useful
in the treatment of patients with myocardial
infarction and have been shown to prolong
survival (for example, metoprolol).
In patients with classic angina (effort-induced angina),
β-blockers can be used with nitrates to increase
exercise duration and tolerance.

They are, however, contraindicated in patients with

asthma, diabetes, severe bradycardia, peripheral
vascular disease, and chronic obstructive
pulmonary disease. [Note: It is important not to discontinue β-blocker
therapy abruptly. The dose should be gradually tapered off over 2 to 3 weeks to
avoid rebound angina, myocardial infarction, and hypertension.]
The prototype β-blocker is propranolol , which acts at both β1
and β2 receptors. Selective blockers of β1 receptors, such as
metoprolol and atenolol, are among the most commonly
prescribed β-blockers.

Nebivolol is a selective blocker of β1 receptors, which also

increases the production of nitric oxide leading to
vasodilation. The selective β-blockers may be administered
cautiously to patients who also have asthma. The nonselective
β-blockers, such as propranolol and nadolol, are
contraindicated due to their blockade of β2-mediated
bronchodilation.
  blocker
• Efek menguntungkan β blocker terutama
terkait dg efek hemodinamiknya:
• Me denyut jantung, TD & kontraktilitas
me kebutuhan O2 miokard pd waktu istirahat
& slm latihan
• Frekuensi denyut jantung yg rendah pe wkt
perfusi diastolik  me perfusi miokard
• Jg me perfusi daerah iskemik krn pe↓ frek
denyut jantung, meningkatkan durasi diastol &
waktu yg tersedia utk aliran darah ke a.
koroner
  blocker
• Berguna mengobati iskemia diam/ambulatori (tdk
menyebbkan rasa sakit, terdeteksi oleh timbulnya
tanda ECG tipikal utk iskemia)
• me mortalitas pasien dg infark miokard baru
• memperbaiki kelangsungan hidup & mencegah
stroke pd pasien dg HT
• Druf of Choice: β blocker kardioselektif spt
atenolol & metoprolol
• Semua β blocker harus dihindari pd pasien asma
  blocker
• Efek yg tdk diinginkan
• pe vol akhir diastol yg menyertai
perlambatan denyut jantung & pe wkt
ejeksi
• pe kebthan O2 pd miokard dihub dg
pe vol diastolik vent kiri
• Efek membahayakan tsb dpt diimbangi
dg penggunaan nitrat
  blocker
• ES: insomnia, mimpi buruk, memburuknya
klaudikasio & disfungsi ereksi
• KI: asma, bradikardi parah, penyakatan
atriovenrikuler, sindroma sick sinus & ggl
ventrikuler kiri tak stabil yg parah
 CALCIUM-CHANNEL BLOCKERS
At clinical doses, these agents affect primarily the resistance of
peripheral and coronary arteriolar smooth muscle. Their use
in the treatment of effort-induced angina relies on the
reduction in myocardial oxygen consumption resulting from
decreased afterload. Their efficacy in vasospastic angina is
due to relaxation of the coronary arteries.

[Note: Verapamil mainly affects the myocardium, whereas nifedipine exerts a

greater effect on smooth muscle in the peripheral vasculature. Diltiazem is
intermediate in its actions.] All calcium-channel blockers lower
blood pressure.
 CALCIUM-CHANNEL BLOCKERS
Calcium is essential for muscular contraction. Calcium influx is
increased inischemia because of the membrane
depolarization that hypoxia produces.
In turn, this promotes the activity of several adenosine
triphosphate–consuming enzymes, thereby depleting energy
stores and worsening the ischemia. The calcium-channel
blockers protect the tissue by inhibiting the entrance of
calcium into cardiac and smooth muscle cells of the coronary
and systemic arterial beds. All calcium-channel blockers are,
therefore, arteriolar vasodilators that cause a decrease in
smooth muscle tone and vascular resistance.
 Farmakodinamik
• Konsentrasi Ca intrasel memegang peranan penting
dlm mempertahankan tonus otot polos dan dlm
kontraksi miokard. Ca masuk ke dlm sel mll kanal Ca
sensitif voltase, yg kmdn memicu pelepasan Ca dr
retikulum sarkoplasma & mitokondria me kadar
Ca sitosolik
• Antagonis Ca menghambat masuknya Ca dg
berikatan dg kanal Ca tipe L di jantung & pembuluh
darah koroner & perifer otot polos vaskular
relaksasi, mendilatasi t.u arteriola
CALCIUM-CHANNEL BLOCKERS (Ca Antagonis)

They may worsen heart failure due to their

negative inotropic effect.
[Note: Variant angina caused by spontaneous coronary spasm, either at work
or at rest , rather than by increased myocardial oxygen requirement, is
controlled by organic nitrates or calcium-channel blockers. β-Blockers are
contraindicated.]
• Ca antagonis menghambat kanal Ca pd otot
polos arteri, menyebbkan relaksasi &
vasodilatasi
• Preload tdk terpengaruh scr bermakna
• Kanal Ca pd miokard & jaringan konduksi
jantung jg terpengaruh shg menghasilkan
efek inotropik negatif
• Gol dihidropiridin (nifedipin, amlodipin) memp
efek relatif kecil pd jantung
• Pd dosis terapi, vasodilatasi yg dihasilkan
menyebbkan pe tonus simpatis (takikardi)
Kelas Ca channel blockers
1. Difenilalkilamin: verapamil  verapamil
relatif kardioselektif. Digunakan utk tx
angina, migren, supraventrikuler takiaritmia
2. Benzotiazepin: diltiazem berefek baik pd otot
polos vaskuler maupun otot jantung, tetapi
kurang memberikan efek inotropik negatif
dibandingkan verapamil. Paling sedikit
menimbulkan efek samping.
3. Dihidropiridin:
generasi pertama: nifedipin dan
generasi kedua: amlodipin, felodipin,
nikardipin, nisoldipin
Semua dihidropiridin mempy afinitas lbh besar pd
kanal Ca vaskuler dibanding kanal Ca jantung
terapi hipertensi
 CALCIUM-CHANNEL BLOCKERS
A. Nifedipine
a dihydropyridine derivative, functions mainly as an arteriolar
vasodilator. This drug has minimal effect on cardiac conduction or
heart rate.
is administered orally, usually as extended-release tablets. It undergoes
hepatic metabolism to products that are eliminated in both urine
and feces.
The vasodilation effect of nifedipine is useful in the treatment of variant
angina caused by spontaneous coronary spasm.
can cause flushing, headache, hypotension, and peripheral edema as
side effects of its vasodilation activity. As with all calcium-channel
blockers, constipation is a problem. Because it has little to no
sympathetic antagonistic action, nifedipine may cause reflex
tachycardia if peripheral vasodilation is marked.
[Note: The general consensus is that short-acting dihydropyridines should be avoided in
coronary artery disease because of evidence of an increase in mortality after an MI and an
increase in acute MI in hypertensive patients.]
CALCIUM-CHANNEL BLOCKERS
B. Verapamil
The diphenylalkylamine verapamil slows cardiac atrioventricular
(AV) conduction directly and decreases heart rate, contractility,
blood pressure, and oxygen demand.
causes greater negative inotropic effects than nifedipine, but it is a
weaker vasodilator.
Because the drug is extensively metabolized by the liver, care must
be taken to adjust the dose in patients with liver dysfunction.
is contraindicated in patients with preexisting depressed cardiac
function or AV conduction abnormalities. It also causes
constipation.
should be used with caution in patients taking digoxin, because
verapamil increases digoxin levels.
 CALCIUM-CHANNEL BLOCKERS

C. Diltiazem
has cardiovascular effects that are similar to those of verapamil. Both
drugs slow AV conduction and decrease the rate of firing of the sinus
node pacemaker.

reduces the heart rate, although to a lesser extent than verapamil, and
also decreases blood pressure.

can relieve coronary artery spasm and, therefore, is particularly useful in

patients with variant angina. It is extensively metabolized by the liver.
The incidence of adverse side effects is low (the same as those for
other calcium-channel blockers).
Interactions with other drugs are the same as those indicated for
verapamil.
• Amlodipin, DOA panjang, kurang menyebbkan
takikardi dibanding nifedipin
• Verapamil & diltiazem (<) menekan nodus sinus
menyebbkan bradikardia saat istirahat
• Verapamil lbh terikat pd kanal yg terbuka &
kurang dipengaruhi oleh potensial membran.
Konduksi di NAV lambat & krn efek verapamil
(tdk spt nifedipin) frequency dependent→
efektif memperlambat kec ventrikular pd aritmia
atrial
• Efek inotropik negatif verapamil & diltiazem
scr parsial dihilangkan oleh refleks pe tonus
adrenergik & penurunan afterload
• Diltiazem mempunyai efek pertengahan antara
verapamil & nifedipin & tdk menyebbkan
takikardia shg lbh disukai
• Krn diltiazem memperlambat NSA→ berguna
utk pasien yg tdk dpt diterapi dg β blocker
• Bbrp obat baru spt amlodipin &
nikardipin mempunyai keuntungan berupa
interaksi yg kecil dg obat kardiovask lain
mis. digoksin & warfarin yg sering
digunakan bersama dg Ca channel
blocker
Farmakokinetik
 Clinical uses of calcium antagonists

• Disritmia (verapamil)
- utk memperlambat denyut ventrikel pd
fibrilasi atrial
- mencegah kekambuhan takikardia
supraventrikular
• Hipertensi
• Mencegah angina (biasanya gol dihidropiridin
atau diltiazem)
 Efek samping
• Konstipasi, dizziness, headache, fatigue
• Verapamil harus dihindari pd pasien
gagal jantung kongestif krn efek
inotropik negatifnya
 SODIUM-CHANNEL BLOCKER

A. Ranolazine
Ranolazine inhibits the late phase of the sodium current
(late INa) improving the oxygen supply-and-demand
equation. Inhibition of late INa reduces intracellular
sodium and calcium overload, thereby improving
diastolic function.
Ranolazine is indicated for the treatment of chronic
angina and may be used alone or in combination with
other traditional therapies, but is most often used as
an option in angina patients who have failed all other
antianginal therapies. It is not to be used to treat an
acute attack of angina.