Cardiovascular Drugs.pptx

CARDIOVASCULAR DRUGS Rizal

085299211357 | [email protected]

STIKES Muhammadiyah Manado - 2019

Anatomi Jantung 1. Letak o o o o

Rongga dada kiri Terlindung dada Ukuran 12-14 x 8-9 x 6 cm Berat 250-350 gm

2. Bagian o Atrium o Ventrikel o Nodal tissue & serat penghantar Khusus [Sino Atrial Node(SA node), Atrio

Ventricular Node (AV node), Bundle of His, Sistem Purkinje]

1. Obat Hipertensi 2. Obat Hipotensi

3. PJK – Antiplatelet & Antikoagulan 4. Obat Gagal Jantung 4. Obat Aritmia Jantung

HIPERTENSI

Classification of Hypertension Classification

SBP and DBP in Adults (mmHg)

Normal Pre Hypertension

<120/ 80 120-139/ 80-89

Hypertension Stage 1 Hypertension Stage 2 Hypertensive Crises Hypertensive Emergency

140-159/ 90-99 ≥160/ ≥100

Hypertensive Urgency

BP > 180/120 mmHg without acute or progressing target-organ damage

BP > 180/120 mmHg with acute or progressing target-organ damage

Mechanism of Short Term Regulation of Blood Pressure

Strategi untuk Menurunkan Tekanan Darah Mengurangi curah jantung (Cardiac Output) • Mengurangi volume darah • Mengurangi denyut jantung

• Mengurangi volume sekuncup jantung (stroke volume)

Mengurangi tahanan vaskuler (Systemic Vascular Resistance)

• Mendilatasi vasculature/pembuluh darah systemic

o Curah jantung/ Cardiac Output adalah volume darah yang dipompa oleh jantung dalam satu menit (mL darah/menit). o Curah jantung (mL/menit) = frekuensi jantung (denyut/menit) X volume

sekuncup (mL/denyut) • Keadaan istirahat : • Frekuensi jantung: 70 denyut/menit

• Volume sekuncup : 70 mL/denyut. • Jadi, curah jantung manusia dalam keadaan istirahat ialah: • Curah jantung = 70 denyut/menit X 70 mL/denyut = 4900 mL/menit

o Volume darah total dalam system sirkulasi manusia yaitu rata-rata 5 L(5000 mL).

Obat-obat Antihipertensi 1. Diuretics (thiazide diuretics, loop diuretics, potassium sparing diuretics) 2. Vasodilators a. Alpha-adrenoceptor antagonists (alpha-blockers) b. Angiotensin converting enzyme inhibitors (ACE inhibitors) c. Angiotensin receptor blockers (ARBs) d. Calcium-channel blockers e. Nitrodilators f. Potasium Channel Opener 3. Cardioinhibitory drugs

a. beta-blockers b. calcium-channel blockers

a. Diuretics (thiazide diuretics, loop diuretics, potassium sparing diuretics)

o Mengurangi cairan tubuh  mengurangi volume darah  menurunkan tekanan darah o Target aksinya pada proses eliminasi oleh ginjal

o Proses eliminasi ginjal meliputi: • Filtrasi glomerulus • Sekresi tubular aktif

• Reabsorpsi tubular pasif o Cnth obat  Telah dbahas

b. Alpha-adrenoceptor antagonists (alpha-blockers) • Reseptor α1 adrenergik banyak terdistribusi pada pembuluh darah • Jika diaktivasi  vasokonstriksi • Alfa bloker : menghambat vasokonstriksi

Contoh: • Selektif α1 : prazosin, terazosin, doxazosin, trimazosin

• Tidak selektif : fenoksibenzamin, fentolamin

c. Beta Bloker  Reseptor beta adrenergik banyak dijumpai pada jantung  Aktivasinya akan menyebabkan efek peningkatan frekuensi denyut jantung (kronotropik positif) dan peningkatan kekuatan kontraksi jantung (inotropik positif)  Obat golongan beta bloker akan memblokade aksi simpatik di reseptor beta

 bradikardi, penurunan volume sekuncup  tekanan darah turun  Contoh: • Non-selektif β1/β2 : propanolol, carvedilol, labetalol, sotalol, nadolol • Selektif β1: acebutolol, atenolol, bisoprolol, metoprolol, esmolol

c. Beta Bloker Aktivasi reseptor β1 dan β2 di jantung, dan β2 di pembuluh darah

Mekanisme utama beta adrenergik mengatur tekanan darah

Sangat sedikit pengaruhnya terhadaptekanan darah

d. Calcium Channel Blocker Efek CCB :

Contoh obatnya

1. Cardiac effects

• Amlodipine

• Decrease contractility

• Felodipine

(negative inotropy)

• Isradipine

• Decrease heart rate (negative chronotropy)

2. Vascular effects • Smooth muscle relaxation vasodilation)

• Nicardipine • Nifedipine • Nimodipine • Nitrendipine • Verapamil • Diltiazem

d. Calcium Channel Blocker Calcium berperan dalam kontraksi otot polos vaskuler

e. ACE Inhibitor Captopril Enalapril Lisinopril

Ramipril Quinapril Trandolapril Fosinopril Benazepril

e. Angiotensin Reseptor Bloker (ARB) Contoh : • Candesartan, • Eprosartan,

• Irbesartan, • Losartan, • Olmesartan,

• Telmisartan, • Valsartan

The Role of RAAS in Normal Regulation of Blood Pressure

f. Vasodilator Nitrat o Senyawa nitrat melepaskan NO  mengaktifkan guanilat siklase  menghasilkan cGMP (siklik GMP)  relaksasi otot  vasodilatasi o Lebih signifikan efeknya pada vena o Venous return dan arterial afterload turun  kerja jantung turun  kebutuhan oksigen seimbang  mencegah spasme coroner o Contoh: Isosorbitdinitrat (ISDN), isosorbitmononitrat, hydralazin, Isorbit, Isordil

g. Pembuka Kanal Kalium

Contoh obat : minoksidil, kromakalim, levkromakalim

HIPOTENSI

Hipotensi o Keadaan di mana tekanan systolic < 90, dan/atau tekanan diastolic pressure < 60 mmHg o Hipotensi dapat terjadi karena : • cardiogenic shock, circulatory shock (including septic), hemorrhagic shock, hypotension that sometimes occurs during surgical anesthesia, etc. • Seringkali merupakan kondisi darurat  perlu penanganan segera

• Perlu obat-obat pressor tekanan darah

Strategi untuk Mengatasi Hipotensi o Meningkatkan Cardiac Output • Increase blood volume (intravenous fluids) • Stimulate contractility (inotropic drugs)

o Increase Systemic Vascular Resistance • Vasocontrictor Drug

Obat-obat antihipotensi Simpatomimetik yang Bekerja Pada o

Reseptor adrenergik α1  vasokonstriksi (Fenilefrin,

Metoksamin) o

Reseptor adrenergik β1  inotropik positif terhadap

jantung (epinefrin, norepinefrin, dobutamin) o

Reseptor Dopamin  Vasokontriksi (Dopamin)

ACUTE CORONARY SYNDROME (ACS)

Overview of Antiplatelet and Anticoagulan

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ACUTE CORONARY SYNDROME Disease of the large and medium-sized arteries 1. Disease of the coronary arteries due to atheroma and its complication, particularly thrombosis 2,3.

The number one killer in the United States and world wide. Every minute, an American dies of coronary heart disease. Coronary heart disease afflicts nearly 16 million Americans and the prevalence rises steadily with age 3.

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Unstable Plaque

Stable Plaque

Plaque rupture Thrombus formation

ECG

Non ST Elevation Normal Cardiac biomarkers (Troponin, CKMB Normal)

ST Elevation Elevated Cardiac biomarkers (Troponin, CKMB)

Non Q wave MI

Unstable Angina (UA)

ECG

Non ST elevation myocardial infarction (NSTEMI)

Q wave MI

ST elevation myocardial infarction (STEMI)

Loscalzo, J., 2010. HARRISON’S Cardiovascular Medicine. New York: The McGraw-Hill Companies Inc. 33 Papadakis, M. & McPhee, S., 2016. CURRENT Medical Diagnosis & Treatment. 55th penyunt. New York: McGraw-Hill Education.

Atherosclerosis is characterized by a thickening of the portion of the arteries wall closest to the lumen with plaque made up: 1.Large number of cells (macrophage, lymphocytes). 2.Deposits of cholesterol and other fatty substances. 3.Dense layers of connective tissue matrix. Widmaier, E., Hershel, R. & Kevin, T., 2014. Vander's Human Physiology The Mechanism of Body Function. 13th penyunt. USA: The 34 McGraw-Hill . Walker, B., Colledge, N., Ralston, S. & Penman, I., 2014. Davidson's Principle and Practice of Medicine 22nd Edition. London: Elsevier.

Heathy Artery  PGI2  NO  ADP diphosphatase  Heparin Sulfat  Thrombomodulin  t. PA (tissue plasminogen activator) Vascular Damage  Increase expression of vWF (von Wilbrand Factor)   Selectin  Tissue Factor  Integrin v3  Fibronectin  Plasminogen activator inhibitor 35

Heathy Artery

 PGI2, NO, and ADP Diphosphatase  antiplatelet agent which are produce normally by endothelial cell. PGI2, NO, ADP diphosphatase are vasodilators  Heparin Sulfat (HS)  chemical sustance that produce by healty endothelial cell, Heparin sulfate will bind with Antithrombin III (produced by liver)  inactivated thrombin molecule, factor Xa, and inactivated factor IX  Thrombomodulin  Molecule that express by healthy endothelial cell  thrombomodulin will bind with thrombin  activated protein C  inactivated factor Va (proaccerin) and VIIIa (AHF-A)  t.PA (tissue plasminogen activator)  convert plasminogen (produced by liver) to plasmin, plasmin will take fibrin strand to FDP (fibrin degradation product)

Heathy Artery

Produced antithrombotik (antiplatelet and anticoagulant)

Heyden, R. et al., 2016. Anatomy and Physiology. USA: University of North Carolina. Widmaier, E., Hershel, R. & Kevin, T., 2014. Vander's Human Physiology The Mechanism of Body Function. 13th penyunt. USA: 36The McGraw-Hill .

Vascular Damage  release chemical substance: vWF (von Wilbrand Factor)  stick on extracellular matrix and will bind with platelet by Glicoprotein Ib (GP1b) receptor  vWF + GPIb will activated : a. Activated phospholipase A2 COX (cyclooxygenase)

Arachidonic acid Aspirin (ASA)

TxA2 (thromboxan A2) (vasocontrictor,  platelet agregation)

b.  (alpha) granuls and  (delta) granul  granuls  Serotonin (5HT), ADP as a platelet agregator, and Ca2+ Ticlopidin, Clopidogrel, Prasugrel, Ticagrelor  granuls  release Coagulation factors (Factor V, VIII); release fibrinogen; PDGF (Platelet Device Growth Factor) c. Tissue Factor  activated coagulation by extrinsic pathway Michelson, A., 2013. Platelets. New York: Elsivier inc. Walker, B., Colledge, N., Ralston, S. & Penman, I., 2014. Davidson's Principle and Practice of Medicine 22nd Edition. London: Elsevier.

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ROS (Reactive Oxygen Species), Hipertension, type 2 Diabetes Mellitus, smoking, Hiperlipidemia, genetik factor, trauma, radiation, sitokin/inflamasi, antibody compex, aging Endothelial disfunction  intima endothelial lesions “fatty streak”  lipoprotein (HDL) on intima   endothelial permeability Lipoprotein oxidation process Accumulation of leukocytes - Phagocytosis oxidized lipoproteins - Infllamatory reaction pro inflamatory cytokines (IL-1, TNF α)

Increase local production of PDGF (platelet derived growth factor) 38

Foam cell formation Lysis of extracellullar matrix •  concentration of antithrombotic substance (NO, PGI2, ADP diphosphatase, Heparin sulfate, Thrombomodulin, and t.PA •  expression of vWF, coagulation factor Platelet adhesion with vWF by GP Ib receptor  TxA2, ADP-P2Y2 receptor, 5HT

Intrinsic pathway (Factor XIIa, XIa, IXa)

Extrinsic pathway (Factor VIIa)

Heparin (Xa, IX, XIIa) Warfarin (VII, IX, X)

Factor Xa ASA (COX), Clopidogrel, prasugrel (P2Y2)

LMWH (Enoxaparin, 39 Fondaparinux)

 Platelet agregation by GPIIb/IIIa receptor

Abciximab, Tirofaban, Eptifibatide, cilostazol (PDE3A)

Factor Xa

Prothrombine

Thrombine FDP (Fibrin Degradation Product)

Fibrinogen

Thrombus Loscalzo, J., 2010. HARRISON’S Cardiovascular Medicine. New York: The McGraw-Hill Companies Inc. Michelson, A., 2013. Platelets. New York: Elsivier inc Papadakis, M. & McPhee, S., 2016. CURRENT Medical Diagnosis & Treatment. 55th penyunt. New York: McGraw-Hill Education. Walksman, R., Gurbel, P. & Gaglia, M., 2014. Antiplatelet Therapy in Cardiovascular Disease. UK: John Wiley & Sons, Ltd.

Fibrin

Plasminogen  Plasmin

• tPA (alteplase, reteplase, tenecteplase) • u-PA (urokinase) • Streptokinase 40

Clopidogrel, Prasugrel, Ticagrelor

Abciximab, Tirofiban, Eptifibatide

Walksman, R., Gurbel, P. & Gaglia, M., 2014. Antiplatelet Therapy in Cardiovascular Disease. UK: John Wiley & 41 Sons, Ltd.

Platelet Receptor COX – 1

P2Y12 / ADP

GPIIB/IIIa

PAR-1

Drugs

Adverse Effect

Aspirin

GI pain, ulceration, bleeding, angioedema, etc.

Ticlopidin

Bleeding, anemia, pain, etc

Clopidogrel

Ulceration, bleeding, pain, agranulocytosis, etc

Prasugrel

Bleeding, anemia, pain, headache, hemolysis, etc.

Ticagrelor Abciximab

Bleeding, dyspnea, pain, headache, etc. Bleeding, pain, hypotension, anemia, etc.

Tirofiban

Bleeding, pain, edema, etc.

Eptifibatide

Bleeding, hipotension, GI hemorrhage, etc.

Vorapaxar Atopaxar

1) COX1= Cyclooxygenase 1; ADP= adenosine diphosphate; GPIIB/IIIA= Glycoprotein IIB/IIIA; PDE3A= phosphodiesterase 3A; cAMP= cyclic adenosine monophosphate; PKA= protein kinase A; PAR-1= Protease-activated receptor 1; GPVI= Glycoprotein VI; GPIb= Glycoprotein IB; vWF= von Willebrand factor 2) * = Secondary prevention of atherothrombotic event 42

Papadakis, M. & McPhee, S., 2016. CURRENT Medical Diagnosis & Treatment. 55th penyunt. New York: McGraw-Hill Education. Innes, J. & Maxwell, S., 2016. Davidson’s Essentials of Medicine. 2nd penyunt. New York: Elsevier Ltd.

1. Anti-anginal therapy Sublingual GTN is valuable first aid in unstable angina, and IV nitrates are useful for the treatment of LV failure and the relief of recurrent or persistent ischaemic pain. 2. Reperfusion therapy • Primary percutaneous coronary intervention (PCI)

• Thrombolysis Innes, J. & Maxwell, S., 2016. Davidson’s Essentials of Medicine. 2nd 43 penyunt. New York: Elsevier Ltd.

GAGAL JANTUNG

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Gagal Jantung o Keadaan di mana jantung gagal memompa cukup darah untuk kebutuhan tubuh o Penyebab Gagal jantung, a.l: • Myocardial infarction • Coronary atery disease • Valve disease • Idiopathic cardiomyopathy • Viral or bacterial cardiomyopathy • Myocarditis • Pericarditis • Arrhythmias • Chronic hypertension • Septic shock

Strategi Penanganan Gagal Jantung o Diuretics • thiazide diuretics • loop diuretics • natriuretic peptides o Vasodilators (dilate arteries and veins) • (ACE) inhibitors • angiotensin receptor blockers • direct acting arterial dilators • Nitrodilators • phosphodiesterase inhibitors

o Cardiostimulatory or inotropic drugs (stimulate contractility) • Digitalis • beta-agonists • phosphodiesterase inhibitors o Cardioinhibitory • beta-blockers • calcium-channel blockers (for diastolic dysfunction)

Inhibitor Fosfodiesterase-3 (PDE-3) Contoh Obat Milrinone dan Amrinone

Memperkuat Kontraksi Otot Jantung

Kardiotonik Meningkatkan Kontraksi Otot Jantung (Inotropik Positif) Contoh: Digoxin Digitoxin Ouabin • Menghambat Na/K ATPase  menghambat pengeluaran Na  Na Intrasel meningkat • Gradien konsentrasi Ca dan Na berkurang  pengeluaran Ca berkurang  Ca intrasel meningkat  kontraksi

ARITMIA JANTUNG

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Aritmia Jantung o o o o

Ketidaknormalan atau ketidakteraturan detak jantung Detak jantung normal : 60 - 100 bpm. Kurang dari 60 bpm  bradikardia  bradiaritmia Lebih dari 100 bpm  takikardia  takiaritmia

Anti Aritmia Jantung 1. Class I – Sodium Channel Blocker 5. Miscellanous • Quinidine, (Ib) Lidocaine, (Ic) • Adenosine Flecainide • Electrolyte supplement 2. Class II – Beta Blocker (magnesium and potassium • Propranolol, Atenolol salts) 3. Class III – Potasium Channel • Digitalis compounds Blocker (cardiac glycosides) • Amiodaron, sotalol, • Atropine (muscarinic receptor antagonist) 4. Class IV – Calcium Channel Blocker • Verapamil

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