ANTI ANGINA

Hany Yusmaini dr Mkes

Dept Farmakologi FKUPN Veteran Jakarta

ANGINA PECTORIS
Manifested by sudden, severe, pressing
substernal pain that often radiates to the left
shoulder and along the flexor surface of the left
arm.
Usually precipitated by exercise, excitement or
a heavy meal.

TYPE OF ANGINA PECTORIS

1.

CLASSIC ANGINA

2.

PRINZMETALS

3.

Atherosklerosis
Precipitating factor (+)
Vasospasm
Precipitating factor (-)

UNSTABLE
A rapid increase in frequency and intensity of
anginal pain occurs, which is thought to herald
imminent myocardial infection.

TYPES OF ANGINA
1.

Classical angina:

2.

Stable
Unstable

Variant or Prinzmetal`s angina

Myocardial infarction what is it ?

Acute and complete occlusion of a coronary artery

Due to coronary thrombosis

STABLE ANGINA

Stable angina is also known as:

Exertional

angina/Typical or classic angina/Angina of

effort/Atherosclerotic angina

The underlying pathology is usually atherosclerosis

(reduced oxygen delivery) giving rise to ischemia
under conditions where the work load on the heart
increases (increased oxygen demand)

Anginal episodes can be precipitated by exercise,

cold, stress, emotion, or eating

UNSTABLE ANGINA

Unstable angina is also known as:

Preinfarction angina
Crescendo angina
Angina at rest

Caused by recurrent episodes of small platelet

clots at the site of a ruptured atherosclerotic
plaque which can also precipitate local
vasospasm
Associated with a change in the character,
frequency, and duration of angina in patients
with stable angina, and episodes of angina at
rest
May be associated with myocardial infarction

VASOSPASTIC ANGINA

Vasospastic angina (uncommon form) is also

known as:
Variant angina
Prinzmetal's angina

Caused by transient vasospasm of the

coronary vessels
Attack occurs even at rest or during sleep
Chest pain may develop at rest

Angina Pectoris

PATHOPHYSIOLOGY

O2 supply

O2 demand
Precipitating factors

ISCHEMIA
PAIN

sehat

angina

angina

Angina Pectoris

RISK FACTOR

Age

Smoking
DM
Genetic ?

Hypertension
Hypercholesterolemia
Oral contraception

atherosklerosis

OBSTRUCTION (a.coronary)
Decreased 02 supply

PRINCIPLES IN THE TREATMENT OF ANGINA

PECTORIS
1.

O2 supply to the tissue

2.

O2 demand of the tissue

3.

risk factor

ANTIANGINAL AGENTS
Three major classes of agents are used individually or
in combination to treat angina:
1.

2.

3.

Organic nitrates:

Vasodilate coronary arteries

Reduce preload and aferload

Calcium channel blockers:

Vasodilate coronary arteries

Reduce afterload
The non-dihydropyridines (verapamil and diltiazem) also
decrease heart rate and contractility

Beta-adrenergic blockers:

Decrease heart rate and contractility - decrease in cardiac

work and O2 consumption
Improve myocardial perfusion due to decrease in heart rate
decreased in ventricular wall tensi

CLASSIFICATION OF
ANTIANGINAL AGENTS
1.

Nitrates
a)
b)

2.

Short acting (10 minutes): Glyceryl trinitrate (GTN and

Nitroglycerine) - EMERGENCY
Long acting (1 Hour): Isosorbide dinitrate, Isosorbide
mononitrate

Calcium Channel Blockers:

a)
b)

Non dihydropyridines : Verapamil, Diltiazem

Dihydropyridines: Nifedipine, Felodipine, Amlodipine,
Nitrendipine
and Nimodipine

3.

Betaadrenergic Blockers: Propranolol, Metoprolol,

Atenolol and others

4.

Others: Antiplatelet, antikoagulan, trombolitik/

fibrinolitik

NITRATES

All Nitrates share same action only

difference is on Pharmacokinetic
properties (duration of action and onset)
Hepatic first-pass metabolism is high and
oral bioavailability is low for nitroglycerin
(GTN) and isosorbide dinitrate (ISDN)
Sublingual

or transdermal administration of
these agents avoids the first-pass effect

Isosorbide mononitrate is not subject to

first-pass metabolism and is 100%
available after oral administration
Hepatic blood flow and disease can affect
the pharmacokinetics of GTN and ISDN

Mechanism of Action of Nitrovasodilators

Nitrates become denitrated by glutathione S-transferase
to release
Nitric Oxide
activates
Guanylate Cyclase*
converts
GTP

cGMP
activates
cGMP-dependent protein kinase

Activation of PKG results in phosphorylation

of several proteins that reduce intracellular calcium
causing smooth muscle relaxation

Mekanisme anti angina

Efek langsung
Dilatasi arteri koroner suplai O2

Efek tak langsung

Venodilatasi preload
Arteriodilatasi afterload
Ejection time berkurang
kebutuhan O2 miokard

Pada dosis besar:

Tekanan darah aliran darah koroner
(suplai)
Reflek takikardi kebutuhan O2 miokard
Dapat terjadi ANGINA PARADOKSAL

Farmakokinetik
Mudah diabsorpsi saluran cerna, mukosa dan kulit
First pass metabolism besar pada pemberian per
oral bioavailabilitas bervariasi
Pemberian sublingual/spray/iv dapat menghindari
first pass metabolism
Transdermal: absorpsi lambat, tapi dapat bertahan
24 jam
Pemberian jangka panjang dapat menimbulkan
toleransi
Penghentian mendadak dapat menimbulkan rebound
phenomen

NITRATES
Pharmacokinetic
Comparison:
Bioavailability:
NG: Below 1%
IDN: 20%
ISMN: 100%

Plasma clearance:
NG: 50L/min
IDN: 4L/min
ISMN: 0.6L/min

 Indikasi:
Angina stabil
Angina tidak stabil
Angina Variant

Serangan akut: Nitrat kerja cepat (sublingual, iv)

Terapi kronik: Nitrat kerja sedang/lambat (oral,
transdermal)

Gagal jantung kongestif

Infark miokard

Efek samping
Efek samping nitrat, terutama disebabkan oleh
vasodilatasi eksesif pembuluh darah :
Sakit kepala, sinkope, dizzines
Takikardi, hipotensi ortostatik
Angina paradoksal
Flushing
Fenomena rebound pada penghentian
mendadak

 Kontraindikasi

Hipersensitivitas terhadap nitrat

Hati-hati pada:

Peningkatan tekanan intrakranial

Hipotensi, hipovolemia
Takiaritmia
Kombinasi dengan vasodilator lain

NITRATE TOLERANCE

Continuous or frequent exposure to

nitrates can lead to the development of
complete tolerance
The mechanism of tolerance is not
completely understood:
May

be related to the enzymes involved in

converting the nitrates to NO
or to the enzyme that produces cGMP

Industrial (occupational) exposure to

organic nitrates has been associated
with Monday disease and physical
dependence manifest by variant angina
occurring 1-2 days after withdrawal

NITRAT ORGANIK

Amilnitrit: inhalasi
Nitrogliserin: oral, parenteral, spray, transdermal
Isosorbid mononitrat (ISMO): oral
Isosorbid dinitrat (ISDN): oral
Penta eritritol tetra nitrat: oral

Drug

Usual single dose

Route of
administration

Duration of action

Short acting
Nitroglycerin

0.15-1.2 mg

sublingual

10 - 30 min

Isosorbide dinitrate

2.5-5 mg

sublingual

10 60 min

Amyl nitrite

0.18 3 ml

inhalation

3 5 min

Long acting
Nitroglycerin sustained
action

6.5 13 mg q 6-8 hrs

oral

6 8 hrs

Nitroglycerin 2%
ointment

1 1.5 inches q hr

topical

3 6 hrs

Niroglycerin slow
released

1 2 mg per 4 hrs

Buccal mucosa

3 6 hrs

transdermal

8 10 hrs

Nitroglycerin
released

slow 10 25 mg /24hrs (one

patch/day}

Isosorbide dinitrate

2.5 10 mg per 2 hrs

sublingual

1.5 2 hrs

Isosorbide dinitrate

10 60 mg per 4-6 hrs

oral

4 6 hrs

Isosorbide dinitrate
chewable

5 10 mg per 2-4 hrs

oral

2 3 hrs

Isosorbide mononitrate

20 mg per 12 hrs

oral

6 10 hrs

ANTAGONIS KALSIUM
1. Golongan dihidropiridin
Nifedipin, nicardipin, nimodipin, felodipin,
amlodipin, nitrendipin, lacidipin

2. Golongan fenilalkilamin: Verapamil

3. Golongan benzotiazepin: Diltiazem
Mekanisme kerja:
Menghambat masuknya kalsium ke dalam sel
Pembuluh darah: Vasodilatasi
Miokard: inotropik negatif
Nodus SA, nodus AV: kronotropik,
dromotropik negatif

CCB

MECHANISM OF ACTION

Inhibit the influx of Calcium into CARDIAC &

VASCULAR cells
MUSCLE TONE

CCB

EFFECTS (I)
Cardiac Effects

Vascular Effects

Heart Rate

Vasodilatation

O2 supply

After load

O2 demand

BP

Conduction

Contraction

O2 demand

CCB

EFFECTS (II)
Phenylalkylamines

A (Verapamil)

Dihydropyridines
B(Nifedipine)

C(Nimodipine)

Benzothiaz
epines
D
(Diltiazem)

Vasodilatation
Peripheral
Coronary
Cerebral

Heart Rate
SA Node
AV Node
Contractility

++
++
+

+++
+++
+

+
+
+++
-

+
+++
+

ANTAGONIS KALSIUM
Efek kardiovaskular

Nifedipin

Verapamil

Diltiazem

(N)

(V)

(D)

1. Vasodilatasi koroner

2. Vasodilatasi perifer

3. Inotropik negatif

4. Kronotropik negatif

5. Dromotropik negatif
6. Refleks takikardi

0
3

5
0

4
0

Mekanisme anti angina

NIFEDIPIN
Efek langsung:
Dilatasi koroner suplai O2

Efek tak langsung:

Resistensi perifer , TD kebutuhan O2 miokard

Dapat terjadi refleks takikardi dan

angina paradoksal

VERAPAMIL DILTIAZEM
Efek langsung:
Inotropik, kronotropik (-) kebutuhan O2 miokard

Efek tak langsung:

Inotropik (-) tegangan dinding ventrikel
Kronotropik (-) waktu pengisian arteri koroner

BETA-BLOCKERS

Though most beta-blockers do not cause

coronary vasodilatation like the
nitrovasodilators or calcium channel
blockers, beta-blockers are important in
the treatment of angina because of their
effects on the heart

 Efek langsung:
Kronotropik & inotropik negatif
menurunkan kebutuhan O2 miokard

Efek tak langsung:

Inotropik (-) mengurangi tegangan
dinding ventrikel
Kronotropik (-) memeprpanjang waktu
diastol pegisian a. koroner (suplai )

Indikasi: Angina stabil kronik

PROPANOLOL

Is the prototype adrenergic blocker

Adrenergic
blocker

Inotropic
chronotropic
domotropic

O2 demand

Renin Ag peripheral BP
resistance
aldosteron
Sodium, water
retention

BP

OBAT LAIN PADA

ANGINA DAN
SINDROM KORENER
AKUT
Antiplatelet

(antitrombosit)
Antikoagulan
Fibrinolitik (trombolitik)

ANTIPLATELETS, ANTICOAGULANT,
THROMBOLYTIC

Antiplatelets:

Anticoagulants:

Drugs that prevent platelet adhesion, activation,

and aggregation
Drugs that prevent blood coagulation cascade
through modification of coagulation factors

Thrombolytics/ fibrinolytics:

Drugs that degrade the thrombus

36

ANTIPLATELET
Platelet:
ADP-receptor

Dense Particle:
ADP, Thromboxane
A2, serotonin

Glycoprotein
IIb/IIIa:
fibrinogen
receptor

Receptor of v WF(Gp Ib
receptor) collagen

37

Platelet activation:
Platelet adhesion
Injured

endothelium releases von Willebrand factor

(collagen receptor)

Platelet activation by:

Thrombin,

ADP, serotonin, thromboxane A2

Activation of receptors on platelet surface:

TxA2 receptor, ADP-receptor, Glycoprotein IIb/IIIa receptor

(fibrinogen receptor)

Platelet aggregation

Linking of platelet by fibrinogen

38

PLATELET ACTIVATION

39

ANTI PLATELET
1. Inhibitor of Cyclooxygenase: ASPIRIN
AA ------------ Thromboxane-A2
COX

irreversibly blocks COX-1 in the platelet TxA2

Prevent platelet activation by TxA2
Also inhibits formation of PGs in gastric mucosa
irritation
Should be given immediately in acute coronary syndrome
Life long use in all ischemic vascular disease (coronary,
cerebral, peripheral)
Aspirin

40

ANTI PLATELETS
2.

ADP-receptor blockers:

Ticlopidin
Reduce

platelet activation by ADP

No gastric irritation
Side effects: neutropenia, liver abnormalities, thrombotic
thrombocytopenia

Clopidogrel
Less

side effects, but costs much more

Faster onset of action
Less GI adverse effects
Now become standard therapy in acute coronary syndrome.

41

ANTI PLATELETS
3. Gp IIb/IIIa receptor blockers:
abciximab,

eptifibatide, lamifiban, tirofiban

Prevent the final step in platelet aggregation
To be administered Intravenously
Only for limited time and not routinely used

Contraindication
Active

bleeding or potentially bleeding

Thrombocytopenia

42

ANTICOAGULANTS
Heparine routinely used in ACS
Unfractionated

heparine (UFH)
Low molecular weight heparine (LMWH):

Fraxiparine, nadroparine, enoxaparine, dalteparine

Synthetic

pentasaccharide: Fondaparinux

Mechanisms of action:
to antithrombin inactivate of F Xa and F IIa.
Fondaparinux inactivate F Xa only
Binds

43

KINETICS

Should be administeed parenterally (iv, sc)

UFH need monitoring of effects (aPTT)
LMWH & fondaparinux: no needs of aPTT monitoring
LMWH & fonaparinux have a longer half life once
or twice daily
Do not cross placental barrier safe for pregnant
women
Antidote of heparine toxicity: Protamine sulphate

44

Side effects
Bleeding
Thrombocytopenia

Contraindication
Active

bleeding, haemophilia, severe hypertension,

intracranial hemorrhage, advance hepatic or renal
disease, threatened abortion

45

ORAL ANTICOAGULANT
Warfarin, dicumarol

vitamine K antagonist inhibits activation of

vit K-dependent factors (II, VII, IX, X)

Delayed onset of action

Administered orally (rarely iv)

Need monitoring of prothrombin time (INR)

Target: INR 1.5 3.5 of normal level (reduction

of PT by 25%)

46

TOXICITY

Warfarin crosses placental barrier readily

hemorrhagic and malformation of the
fetus contraindicated during pregnancy
Rarely: cutaneous necrosis, infarction of
the breast, fatty tissues, intestines,
extremities.
Interact widely with other drugs (NSAID,
vit K, barbiturates, rifampicin, diuretic,
steroids, sulpha, amiodarone, ) and foods
Antidote: Vit K
47

48

THROMBOLYTICS (FIBRINOLYTICS)
Streptokinase
Urokinase
Anistreplase
Alteplase (tPA)

Fibrinogen
Thrombin
Fibrin

Plasminogen

Plasmin
FDP

Main indication: reperfusion in acute STEMI

49

Thrombolytic is only effective in newly formed

thrombus (Less than 6-12 hours)
Administration: iv infusion
STREPTOKINASE
Produced by Steptococcus
UROKINASE
Extrated from human renal cells allergic rx/ rare
ALTEPLASE (tPA)
Naturally occuring fibrinolytic

50

SIDE EFFECTS AND

CONTRAINDICATIONS

Side effects:
Hemorrhage
Hypotension

(Streptokinase)
Allergic reaction (Streptokinase)

Contraindications
Active

bleeding
Any previous history of hemorhagic stroke
Non hemor. Stroke within 1 year
Internal bleeding within 6 mo.
Hypertension (>180/110), pregnancy
Major surgery, trauma
Pregnancy
51