NEW ISSUES IN HYPERTENSION BLOOD PRESSURE CONTROL AND VASCULAR PROTECTION EMERGING ROLE OF CALCIUM CHANNEL BLOCKERS

TERMINOLOGI CA
Senyawa yg mengganggu Ca-dependent pada sel membran/intrasel = Calcium channel antagonist = Calcium entry antagonist = Slow channel antagonist
Fleckenstein (1964) Ca Th. 1970 Ca dipublikasikan Th. 1980-an terapi hipertensi dan penyakit jantung

ANTAGONIS KALSIUM
- Oppie (1988) merupakan anti Hipertensi yg potent baik sebagai monoterapi / kombinasi - Kaplan (1989) terapi pada : Hipertensi refractory Hipertensi tikus - Buhler & Coworker (1982) Respon baik pada Hipertensi lansia dengan - Kelly & OMalley (1992) RAA sistem yang rendah - Chellingsworth et al (1990) : Antagonis kalsium (dihidropiline) mempunyai efek natriuretic yang cukup kuat - Brenner et al (1988) vasodilator di arterioles ginjal GFR meningkat
(Kaplan N.M. Cl Hyp 1994 : 191-280

PERANAN KALSIUM :
ION Ca++ ION Ca++
Fungsi vital sel organ tubuh Peranan dalam kontraksi miokard Peranan dalam tonus vasomotor pembuluh darah Menentukan potensial listrik dan daya hantaran listrik seluler dalam miokard

Influx CA++ ke dalam sel melalui :

1. Voltage dependent slow channel (Plateu phase) 2. Aktivitas oleh adenosine-mono-phosphate (Cyclic AMP) 3. Passive transport

Jalur I : Slow channel dapat dihambat oleh segolongan obat

Calcium channel inhibitor (Calcium antagonist)

Fleckenstein (1971) : Untuk pertama kali membuktikan bahwa influx

calcium kedalam sel dapat dipengaruhi selama phase plateau dari action potential oleh obat calcium antagonist

KANAL KALSIUM PADA MEMBRAN SEL

I. Receptor - Operated Channel (ROC) > depolarisasi (-) II. Voltage - Operated Channel (VOC) > depolarisasi (+) 1. Kanal Neuronal (N) : jaringan saraf 2. Kanal Transient (T) : jaringan konduksi, pacemaker 3. Kanal Long-Lasting (L): jaringan otak, otot polos, jantung, otot rangka

POSSIBLE SITES OF ACTION

ATP Ca2+ RECEPTOR K+ ATP Na+

Ca2+
EXCHANGE CARRIER

Na+

CAM Ca2+ Ca2+PL C-AMP Ca Ca Ca Ca SR Ca

PDE

5- AMP CONTRACTION

MYOFILAMENTS

Ca2+ Ca2+ RELAXATION ?

Mito

Na+

Ca2+

ANGIOTENSIN I

+ ANGIOTENSIN II

ACE INHIBITOR BRADYKININ

Inactive ftacments

PLATELET AGGREGATION

PLATELET AGGREGATION

ENDOTHELIAL CELL LAYER

KINASE ET-1 ET-1 NO ET-1 PG12

VSCULAR SMOOTH MUSCLE CELL

PLC Ca2+ PKC TGF-b1 PKC

bFGP PDGF

cGMP

cAMP

ANTIPROLIFERATION

RELAXATION

CONTRACTION

PROLIFERATION

Atherosclerosis and Blood pressure-induced organ damage

Monocyte 8-iso-PGF2 Adhesion VCAMs ELAMs Endothelial Activation Monocyte LDL LDL Ecto-ADPase

TXA2 Platelets Collagen, PAF PGI2 NO NO

ADP,Trombin,

Chemotoxis

8-iso-PGF2

Prostacyclin NO

Differentiation Macrophage Scavenger receptor

Minimally modified LDL Vasomotor tone Oxidized LDL

Foam cell formation

Smoth muscle cells

Atherosclerosis : Lesion Initiation

Calcium-Dependent Events
Platelet aggregation Platelet agregation Smooth muscle proliferation Smooth muscle cell cell proliferation and and migration migration Monocyte adhesion Monocyte adhesion Release of growth factors Release of growth factors Matrix formation Matrix formationof lesion Calcification Calcification of lesion
Nayler, W.G., J Cardiovasc Pharmacol 1999; 33 (Suppl.2): S7-S11

Plaque Structure and Plaque Structure and Calcium-Dependent Events

Progression of Atherosclerosis
Coronary artery at lesion-prone location Type II lesion Type III (preatheroma)
Adaptive thickening (smooth muscle) Intima Media Macrophage foam cells Small pools of extracellular lipid

Type IV (atheroma)

Type Va (fibroatheroma)

Type VI (complicated lesion)

Core of extracellular lipid

Fibrous thickening

Thrombus Fissure and hematoma

Adapted from Stary, in Fuster et al, eds. Atherosclerosis and Coronary Artery Disease. 1996.

KLASIFIKASI STRUKTUR KIMIA ANTAGONIS KALSIUM

1. Fenilalkilamin : Varapamil (V), Tiapamil

2. Benzotiazepin : Diltiazem (D)

3. Dhidropiridin : Nifedipin (N), Isradipin (I) (DHP) Nitrendipin (Nk), Amlodipin (A) Nimodipin, Felodipin (F) 4. Piperazin : Sinarisin, Lidoflazin Flunarisin

Pharmacologic Effect of Calcium Entry Blockersa

Diltiazem
Heart rate

Verapamil

Dihydropyridine

Myokardial constractility
Nodal conduction Peripheral vasodilation

(Kaplan N.M. Cl Hyp 1994 : 191-280

Selective Calcium Antagonists Antagonist Selective Calcium for Hypertension Hypertension for
Chemical Type Phenylalkylamines Benzothiazepines 1,4-Dihydropyridines Chemical Names Verapamil Diltiazem Nifedipine Nicardipine Isradipine Felodipine Amlodipine Brand Names Calan ,Calan SR, Isoptin SR ,Verelan Cardizem CD , Dila cor XR , Herbesser Adalat CC Procardia XL Cardene DynaCire Plendil Norvasc

Postulated Effect of Agents on on Postulated Effects ofDifferent Different Agents Endothelial Cell Production Endothelial Cell NO NO Production
CCB Kinins ACEI BK2 L-Arginine Statins eNOS ACE NO2 NO + L-Citrulline Inactive peptides

eNOS mRNA Endothelial Cell

Loke et al. Hypertension. 1999;34:5631999;34:563-567; Loke. Loke. Circulation. 1999;100:12911999;100:1291-1297; Laufs et al. Circulation. 1998;97:11291998;97:1129-1135.

CA IN CORONARY ARTERY DISEASES

1. Chronic stable angina
2. Variant or Prinzmetal angina 3. Unstable angina

4. Myocardial infarction
5. Silent failure 6. Heart failure 7. Interventional procedure 8. Prevention of atherosclerosis Ca

CA PADA TERAPI PJK :

1. ME aliran oksigen miokard
Peningkatan aliran darah Melebarkan daerah stenosis Meningkatkan perfusi subendokard Mencegah spasme koroner Menurunkan agregasi trombosit Memperbaiki viskositas darah

2. ME kebutuhan oksigen miokard

Penurunan tahanan tepi Penurunan kontraktilitas Penurunan denyut jantung Penurunan metabolisme intrasel

Rationale for Early Investigations of CCB Antiatherosclerotic Effects

Animal models: decrease in aortic lesion area and cholesterol content in cholesterol-fed rabbits In vitro mechanistic studies consistent with antiatherosclerotic action Inhibited smooth muscle cell migration and proliferation Inhibited accumulation of extracellular matrix and lipid accumulation in foam cells Interacted with lipoprotein metabolic pathways
Weinstein. J Cardiovasc Pharmacol. 1988;12(suppl 6):S29-S35.

PERAN BARU KALSIUM ANTAGONIST

1. Disfungsi endotel NO, Blok endotelin 2. Agregasi platelet Kalsium sitosolik

3. Adheren molekul belum jelas / NO

4. Mutasi monosit Makrofag : endotelin

5. Migrasi dan Proliferasi Sel Otot PDGF, Ca

CALSIUM CHANNEL DEPENDENT AND INDEPENDENT EVENTS IN ATHEROSCLERPSIS

DEPENDENT :
Smooth muscle events : - Contraction - Migration - Proliferation - Transformation Neurotransmitter release Growth factor release Cholesterol processing LDL processing Microphage function

INDEPENDENT :
Endothelial cell function Platelet function

PENELITIAN PERAN BARU KALSIUM ANTAGONIS

1. Mayler (1992) Pengaruh anti aterogenik Kelinci : - Aterosklerotik (12 minggu) - Amlodipin (1 - 5 mg) - Aorta thorakalis Aterosklerosis

2. Kramsch, Sisarma (1995) Pengaruh Ox LDL Kera : - Aterosklerotik - Amlodipin - Ox LDL , Efekhipolipidemik
3. Imtact dan Regress (1990) : Mencegah lesi baru atherosklerosis Tidak meregresi aterosklerosis

RECENT STUDIES REPORTING INCREASED RISK WITH ANTIHYPERTENSIVE DRUGS

Short acting Calcium Antagonist-particulary at high doses-increase MI risk in Hypertensive patients (Psaty et. Al. JAMA 1995; 274 : 629-625) Short acting Nifedipine increase mortality risk in patients with CHD (Furberg et al. Circulation 1995; 92:1326-1331) Short - acting nifedipine has not approved by the Food and Drug Administration of USA for the treatment of hypertension. (Bassett et al. Journal of Hypertension 1997; 15:915-923)

Antiatherosclerotic Effects of CCBs CCBs Antiatherosclerosis Effect of :: PREVENT PREVENT

Randomized, double-blind study of amlodipine besylate 10 mg vs usual care 825 patients with symptomatic CAD 3-year follow-up Prespecified outcome measures Primary: progression of early atherosclerotic segments by QCA Progression of other atherosclerotic segments Carotid atherosclerosis by B-mode carotid ultrasound Clinical events
Byington et al. Am J Cardiol. 1997;80:1087-1090.

PREVENT: Primary QCA Endpoint* PREVENT : Primary QCA Endpoint* Change in MLD Change in MLD
0.15
Mean Change (mm)

Placebo Amlodipine besylate Primary QCA Endpoint

0.10 0.05 0.00 -0.05 -0.10 -0.15

30%

>30% to 50%

>50%

All Segments

* Values are mean SE, adjusted for segment, clinic, and PTCA during baseline angiogram. P=NS for all comparisons of amlodipine besylate versus placebo. Pitt et al. Circulation. 2000;102:1503-1510.

Atherosclerosis by B-Mode Measurement of IMT PREVENT : Effect of Amlodipine on

PREVENT: Effect of on Carotid Carotic Atherosclerosis byAmlodipine B-Mode Measurement of IMT
0.10
(mm) Change (mm) Mean Mean Change 3 Years Years at at 3

Atherosclerosis by B-Mode Measurement Amlodipine of IMT

Placebo Amlodipine P=.007
P=.007 Placebo
0.10

0.05
0.05

0.00 0.00
-0.05

-0.05
-0.10

-0.10
Pitt et al. Circulation. 2000;102:1503-1510.

Carotic Atherosclerosis by B-Mode Ultrasound

0.043
Change in IMT (mm)

PREVENT: Effect of Amlodipine Besylate on PREVENT : Effect of Amlodipine Besylate on Carotid Atherosclerosis by B-Mode Ultrasound
Placebo (n=185)

0.033 0.023 0.013

P=.007 between groups

Amlodipine besylate (n=192)

0.003 0 -0.007 0 12 24 36

N=27,478 observations. Average baseline IMT=0.95 mm. Data on file. Pfizer Inc.

Months

And Major Vascular Procedures by Treatment

Documented Unstable Angina/ Congestive Heart Failure 30.0
Cumulative Event/ Procedure Rate (%)

PREVENT: Hospitalization for Unstable Angina PREVENT : Hospitalization for Unstable Angina and Major Vascular Procedures by Treatment
Any Revascularization 30.0 25.0 Placebo (n=408) 35% 20.0 15.0 Placebo 43% P=.001

25.0 20.0 15.0 10.0 5.0 0.0 0 6 12 18 24 30 36 Months of Follow-up

P=.01 10.0 Amlodipine besylate (n=417) 5.0 0.0 0 6 12 18 24

Amlodipine besylate 30 36

Months of Follow-up

Pitt et al. Circulation. 2000;102:1503-1510.

CAPARES: Effect ofAmlodipine Amlodipine on Restenosis Restenosis CAPARES : Effect of andClinical Clinical Outcomes And Outcomesin inPTCA PTCAPatients Patients
Placebo-controlled, double-blind, randomized, multicenter trial of patients undergoing PTCA Pretreatment with Amlodipine 10 mg (n=318) Placebo (n=317) QCA endpoint: loss in minimal lumen diameter from post-PTCA to follow-up Clinical endpoints Death MI CABG Repeat PTCA
Jrgensen et al. J Am Coll Cardiol. 2000;35:592-599.

CAPARES : Amlodipine Treatment CAPARES : Amlodipine Treatment Reduced Need for Repeat PTCA Reduced Need For Repeat PTCA
Placebo (n=294)

N=635
No. of Events

50 40

Amlodipine (n=291)

P=.007 40

No change in primary endpoint: loss in minimal lumen diameter Significant reduction in composite clinical endpoint and repeat PTCA

P=.011
30

23
20 10 0

20 9

Repeat PTCA

Composite Endpoint (Death, MI, CABG, Repeat PTCA)

Jrgensen et al. J Am Coll Cardiol. 2000;35:592-599.

Amlodipine: Additional Mechanisms Under Investigation May Impact on Atherosclerosis

Membrane-stabilizing effects Inhibition of smooth muscle cell migration/proliferation Increased nitric oxide production

Mason et al. J Mol Cell Cardiol. 1999;31:275-281. Tulenko et al. J Cardiovasc Pharmacol. 1995;26(suppl A):S11-S17. Zhang and Hintze. Circulation. 1998;97:576-580.

BIOEQUIVALENCE TESTING OF AMLODIPINE MALEAT AND BESYLATE

Parameter 1. Tlag (hour) 2. Tmax (hour) Drug A 1.080.008 6.170.21 Drug B 1.250.13 6.250.18

3. Cmax (mg/ml)
4. AUCo+ (mg/ml/hour)

8.260.50
231.8119.75

7.650.52
182.2419.88

Sulamto, S.D., UGM, Nov. 2004

SAFETY RESULT OBTAINED FROM 12 VOLUNTEERS

Drug A Number of subjects At least one adverse event Hypotension* Headache Oedema Fatigue Nausea Flushing Dizziness Dyspnoe 12 3 5 0 0 0 0 0 0 Drug B 12 1 6 0 0 0 0 0 0

Death Discontinue due to adverse events

0 0

0 0

*Hypotension is defined as the decrease of blood pressure more than 20% from the baseline

Sulamto, S.D., UGM, Nov. 2004

AVERAGE PLASMA AMLODIPINE CONCENTRATION (mg/ml) vs. time Curves AFTER SINGLE DOSE OF DRUG A AND DRUG B IN 12 HEALTHY VOLUNTEERS
8 7 Drug A Drug B

6
5 4

3
2 1 4 8 12 24 48 72 95 time (hour)

Sulamto, S.D., UGM, Nov. 2004

AntiatheroscleroticMECHANISMS Mechanisms ANTIATHEROSLEROTIC OF ofCALCIUM Calcium Channel Blockers CHANNEL BLOCKERS

Increased nitric oxide production Reversal of endothelial dysfunction Inhibition of smooth muscle cell migration / proliferation Slowed monocyte infiltration Reduced endothelial adhesion of monocytes Inhibit expression of certain matrix metalloproteinases ( MMP )
Mason RP. Atherosclerosis 2002 ; 165 : 191-199 Nayler, W.G., J Cardiovasc Pharmacol 1999; 33 (Suppl.2): S7-S Mason et al. J Mol Cell Cardiol. 1999 ;31:275-281. Zhang and Hintze. Circulation. 1998 ;97:576-580.

EFFEK KARDIOPROTEKTIF CALSIUM ANTAGONIST

MENURUNKAN KEBUTUHAN OKSIGEN MIOKARDIUM Menurunkan Tekanan Darah Menurunkan Denyut Jantung MENEKAN KERUSAKAN SEL MIOKARDIUM AKIBAT INFLIKS ION CA++ YANG BERLEBIHAN KE DALAM SEL Menekan peningkatan ion Ca++ di dalam sel miokardium Menekan penurunan ATP & CP di dalam sel miokardium MENINGKATKAN PENYEDIAAN OKSIGEN MIOKARDIUM Menghilangkan spasme koroner Meningkatkan aliran darah sub-endokardium Menurunkan denyut jantung (memperpanjang periode diastolik) Menekan sklerosis koroner EFEK : Anti Aritmia

KESIMPULAN :
CA GEN. I : SUDAH MAPAN, CARA KERJA
JELAS

CA GEN. II VASKULOSELEKTIF :
VASODILATOR PILIHAN & EFEKTIF EFEK SAMPING MINIMAL MENGENDALIKAN BP 24 JAM PROFIL HEMODINAMIK MENGUNTUNGKAN EFEK NATRIURETIK & DEURETIK DAPAT MENGREGRESI LVH

PARADIGMA BARU

Terima Kasih