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Hany Yusmaini dr Mkes

Dept Farmakologi FKUPN Veteran Jakarta


 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.
1. CLASSIC ANGINA
 Atherosklerosis
 Precipitating factor (+)
2. PRINZMETALS
 Vasospasm
 Precipitating factor (-)
3. UNSTABLE
A rapid increase in frequency and intensity of
anginal pain occurs, which is thought to herald
imminent myocardial infection.
1. Classical angina:
 Stable
 Unstable
2. Variant or Prinzmetal`s angina

Myocardial infarction – what is it ?


 Acute and complete occlusion of a coronary artery
 Due to coronary thrombosis
 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 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 (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

O2 supply O2 demand

Precipitating factors

ISCHEMIA

PAIN
S D

sehat angina angina


Angina Pectoris

 Age  Hypertension
 Smoking  Hypercholesterolemia
 DM  Oral contraception
 Genetic ?

atherosklerosis

OBSTRUCTION (a.coronary)

Decreased 02 supply
1. O2 supply to the tissue
2. O2 demand of the tissue
3. risk factor
Three major classes of agents are used individually or
in combination to treat angina:

1. Organic nitrates:
 Vasodilate coronary arteries
 Reduce preload and aferload

2. Calcium channel blockers:


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

3. 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
1. Nitrates
a) Short acting (10 minutes): Glyceryl trinitrate (GTN and Nitroglycerine) -
EMERGENCY
b) Long acting (1 Hour): Isosorbide dinitrate, Isosorbide mononitrate

2. Calcium Channel Blockers:


a) Non dihydropyridines : Verapamil, Diltiazem
b) Dihydropyridines: Nifedipine, Felodipine, Amlodipine, Nitrendipine
and Nimodipine

3. Beta—adrenergic Blockers: Propranolol, Metoprolol, Atenolol and


others

4. Others: Antiplatelet, antikoagulan, trombolitik/ fibrinolitik


 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
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
 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 Duration of action
administration
Short acting 0.15-1.2 mg sublingual 10 - 30 min
Nitroglycerin
Isosorbide dinitrate 2.5-5 mg sublingual 10 – 60 min
Amyl nitrite 0.18 – 3 ml inhalation 3 – 5 min
Long acting
Nitroglycerin sustained 6.5 – 13 mg q 6-8 hrs oral 6 – 8 hrs
action
Nitroglycerin 2% 1 – 1.5 inches q hr topical 3 – 6 hrs
ointment
Niroglycerin slow 1 –2 mg per 4 hrs Buccal mucosa 3 – 6 hrs
released
Nitroglycerin slow 10 – 25 mg /24hrs (one transdermal 8 –10 hrs
released 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 5 – 10 mg per 2-4 hrs oral 2 – 3 hrs
chewable
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

 Inhibitthe influx of Calcium into CARDIAC &


VASCULAR cells MUSCLE TONE
CCB

Vascular Effects Cardiac Effects

Vasodilatation Heart Rate  Conduction

 O2 supply After load BP  Contraction

 O2 demand  O2 demand
CCB

Phenylalkylamines Dihydropyridines Benzothiaz


A (Verapamil) epines
B(Nifedipine) C(Nimodipine) 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 5 4 3
2. Vasodilatasi perifer 5 4 3
3. Inotropik negatif 1 4 2
4. Kronotropik negatif 1 5 5
5. Dromotropik negatif 0 5 4
6. Refleks takikardi 3 0 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 
 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
Is the prototype  adrenergic blocker

Inotropic
chronotropic  O2 demand
 Adrenergic domotropic

blocker
Renin  Ag  peripheral BP 
resistance

aldosteron

 Sodium, water BP 
retention
•Antiplatelet (antitrombosit)
•Antikoagulan
•Fibrinolitik (trombolitik)
ANTIPLATELETS, ANTICOAGULANT,
THROMBOLYTIC
• Antiplatelets:
– Drugs that prevent platelet adhesion, activation,
and aggregation
• Anticoagulants:
– Drugs that prevent blood coagulation cascade
through modification of coagulation factors
• Thrombolytics/ fibrinolytics:
– Drugs that degrade the thrombus

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ANTIPLATELET
• Platelet:
ADP-receptor

Glycoprotein
IIb/IIIa:
Dense Particle:
fibrinogen
ADP, Thromboxane
receptor
A2, serotonin

Receptor of v WF(Gp Ib
receptor)  collagen

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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

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PLATELET ACTIVATION

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1. Inhibitor of Cyclooxygenase: ASPIRIN

AA ------------ Thromboxane-A2
COX

 Aspirin 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)

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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.

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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

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Heparine  routinely used in ACS
 Unfractionated heparine (UFH)
 Low molecular weight heparine (LMWH):
 Fraxiparine, nadroparine, enoxaparine, dalteparine …
 Synthetic pentasaccharide: Fondaparinux

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

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 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

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 Side effects
 Bleeding
 Thrombocytopenia
 Contraindication
 Active bleeding, haemophilia, severe hypertension,
intracranial hemorrhage, advance hepatic or renal
disease, threatened abortion …

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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%)

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 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

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Streptokinase Fibrinogen
Urokinase
Anistreplase Thrombin
Alteplase (tPA)
Fibrin

Plasminogen Plasmin

FDP

Main indication: reperfusion in acute STEMI

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 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

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 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

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