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Transcript of FAARMAKOLOGI TOKSIKOLOBGI CACB
FARMAKOLOGI DAN TOKSIKOLOG II
Oleh
Prof. Dr. Urip Harahap, Apt.Drs. Rasmdin Muchtar, MS., Apt
Yuandani, S.Si., M. Si., Apt.Poppy Anjelisa, S.Si., M. Si., Apt.
FAKULTAS FARMASIUNIVERSITAS SUMATERA UTARA
MEDAN 2011
Program Studi : FarmasiSemester : IVA. IVB, DAN IVCKode MK : FKC- 292 (2 SKS)
Urip Harahap - Farmakologi dan Toksikologi II
Garis Besar Materi Kuliah
Pokok Basahan Dosen Penyaji
1. Farmakologi dan Toksikologi Antihipertensi2. Farmakologi dan Toksikologi Diuretika3. Farmakologi dan Toksikologi Antagonis Kalsium4. Farmakologi Toksikologi Antiaritmia5. Farmakologi dan Toksikologi Antingina
Prof. Urip Harahap, Apt.
6. Farmakologi dan Toksikologi Analgetika -Antipiretika Drs. Rasmadin Muchtar, MS., Apt
7. Farmakologi dan Toksikologi Antiinflamasi
8. Farmakologi dan Toksikologi Antidiare9. Farmakologi dan Toksikologi Antidiabetes Yuandani, S. Si., M. Si., Apt.
10. Farmakologi dan Toksikologi Antiparkinson
11. Farmakologi dan Toksikologi Antigout
12. Farmakologi dan Toksikologi Trombolitik Agent Poppy Anjelisa, S. Si., Apt.
13. Farmakologi dan Toksikologi Antihiperlipidemia
14. Farmakologi dan Toksikologi Antihistamin
Urip Harahap - Farmakologi dan Toksikologi II 2
URIP HARAHAP
Urip Harahap - Farmakologi dan Toksikologi II
Farmakologi dan Toksikologi Antagonis Calcium
3
Rujukan
• http://pharmacologycorner.com/calcium-channel-blockers-classification-mechanism-of-action-indications/
Outline
Introduction
CCB binding sites
Heterogeneity of action
Cardiac & hemodynamic
differentiation
Pharmacokinetics
Adverse effects
Contraindications
Summary
ATP ADP
Ca2+
Ca2+
Na+
Ca2+-ATPaseNa+ -driven Ca2+ antiport
2 mM
Ca2+Ca2+
ATP ADP
Ca2+
MitochondriaCa2+-bindingproteins
Ca2+-ATPase
Ca2+-sequestering compartments
Regulation of Ca2+ extrusion
100 nM
RGq
PLCb
IP3DAG
Receptor-dependent Ca2+ entry
Regulation of Ca2+ entry
Voltage-dependent Ca2+ channel Polarized
DepolarizedClosed
Open-activeOpen-inactive
Classification of agents
Chemical Type Chemical Names Brand Names
Phenylalkylamines verapamil Calan,Calna SR,Isoptin SR,Verelan
Benzothiazepines diltiazem Cardizem CD,Dilacor XR
1,4-Dihydropyridines Nifedipine
nicardipineisradipinefelodipineamlodipine
Adalat CC,Procardia XL
CardeneDynaCircPlendilNorvasc
Three Classes of CCBs
Three Classes of CCBs
N CH2 CH2 N
0
CH3
0 C CH3
0
CH3
CH3
Diltiazem
C 0 CH3
NO2
CH3H3C
C0H3C
0 0
Nifedipine
C CH2 CH2 CH2CH2 CH2N
CH3
CH3
C N
CH
H3C
0H3C
0H3C
0 CH3
0 CH3
Verapamil
NH
S
Angina pectoris
Hypertension
Treatment of supraventricular
arrhythmias
- Atrial Flutter
- Atrial Fibrillation
- Paroxysmal SVT
Widespread use of CCBs
Clinical trials have shown that Flunarizine (Sibelium) is an effective prophylactic medication for reducing the frequency of migraine episodes. This drug is not available in the US, its use is common in some European countries and in South America.
Flunarizine is the only calcium channel blocker shown to be effective as prophylactic drug.
Some studies show that flunarizine is as effective as propanolol in reducing severity and frequency of the attacks.
Drugs for migraine prophylaxis
Some studies show that flunarizine is as effective as propanolol in reducing severity and frequency of the attacks.
The recommended flunarizine dose in this setting is of 10 mg/d. The most important adverse effect of flunarizine use is weight gain, which limits patient compliance, specially in women.
Evidence does not support the use of other calcium channel blockers. Nimodipine failed to demonstrate any effects in clinical trials, while there is no convincing evidence of the effect of verapamil.
Drugs for migraine prophylaxis
Outline
Introduction
CCB binding sites
Heterogeneity of action
Cardiac & hemodynamic
differentiation
Pharmacokinetics
Adverse effects
Contraindications
Summary
Ion Ca berperan penting mengatur kontraksi otot rangka dan otot polos, begitu juga pada otot jantung normal atau dalam keadaan sakit ANIMASI\Animasi kontraksi otot\InsectContraction[1].swf, C:\URIP-HARAHAP\ANIMASI\myosin2[1].swf, ANTIPORTER Ca.ppt, mOA kontraksi otot.ppt Klasifikasi CaCB berdasarkan hambatannya terhadap
pergerakan dan ikatan Ca2+ yang digunakan secara klinis , WHO membaginya 2 jenis, yaitu selektif untuk tipe L (cenel Ca2+-voltage dependent) dan yang tidak selektif. CaCB selektif lebih banyak diigunakan dalam praktis
Mekanisme kerja CaCB selektif sebagai antihipertensif adalah dengan cara menghambat influks Ca++ dari ekstraseluler ke intraseluler pembuluh darah melalui cenel L-type relaksasi otot polos pembuluh darah dan mengurangi tahan vaskular.
Pada Otot jantung: • Ca++ berikatan dgn troponin C utk inhibi interaksi aktin-miosin
Otot polos: • Ca++ berikatan dengan kalmodulin untuk mengaktivasi mysin light chain
kinase (MCLK) yang kemudian memfosforilasi P-light chain myosinkontraksi
Regulasi Ca++ -intraseluler (sitoplasmik)
Banyak jenis pompa ion, cenel, dan tempat pertukaran ion yang secara langsung terlibat mengontrol Ca2+di dalam intrasel (tapak tindak obat?)
Ketika istirahat, kadar Ca2+ bebas dalam intrasel <100 nM (normal) sdgkan dalam eksresel >1mM (dipelihara dalam keadaan istirahat, normal). Jika ada stimulasi, kadar Ca++ bebas dlam sitoplasma naik 1uM; ini meningkatkan pembukaan cenel pada sarkolema/plasmolema dan pd sarkoplasmik/retikulum endoplasma.
Jika stimulasi berhenti, pompa ion yang bergantung ATP dan pertukaran Na+/Ca2+ akan kembali ke kadar semula seperti waktu istirahat.
Peran kalsium pada otot jantung dan otot polos
Note: bandingkan degn influks Ca yang mediasikan ligand gate (INFLUKS Ca-SecMes.ppt)
STRKTUR MOLEKUL YANG TERLIBAT MENGATUR Ca2+
Struktur molekul plasmolema/sakolema yang mengatur influks Ca++
•Ada 3 kategori cenel Ca++membolehkan masuk Ca++ ke dlm intrasel− Cenel –voltage dependent− Cenel- receptor operated− Cenel-strectch operatedVoltage (potensial) dependent Ca++-channel (homolog dgn cenel
Na+ dan K+)Jenis L (L-type):
• konduktans besar terus menerus, inaktivasi lambat, tersebar dalam sistem kardiovaskular (SKV), berperan pada fase potensial aksi plateu (slow inward current), memicu rilis Ca++ internal, sensitif terhdap CaCB
• Cenel L-jtg diatur oleh cAMP-dependent protein kinase (fosforilasi yang meningkatkan pembukaan cenel pd membran yang diberi potensial)
STRKTUR MOLEKUL YANG TERLIBAT MENGATUR Ca2+
Jenis T (T-type): • sec struktural tipe-L, inaktivasi cepat, banyak
terdapat pd sel jantung, kurang pd sist tubulus T (jar SA-node), terlibat dlm aktivitas pacemaker jantung, regulasi pertumbuhan, dan pencetusan kontraksi otot polos vaskular, sedikit terdapat dalam miokardium ventrikel dewasa. Sgt tdk sensitif pada kebanyak CaCB-tipe L (kecuali mibefradil)
Jenis N (N-type):• Ditemukan hanya pd sel saraf, sangat tidak
sensitif thd CaCB yang digunakan pada gangguan KV
Receptor-operated Ca++-channel (misalnya R-1-adrenergik: sangat tidak peka dengan CaCBStretch operated atau Leaky Ca-channel (sangat penting untuk memelihara tonus oto polos vaskuler), tidak peka terhadap CaCB
Struktur molekul plasmalema yang bertanggung jawab untuk influks Ca++
Ca++ pumps (ATPases): sec aktif mengekstrusikan Ca++
melawan gradien; bbp bentuk enzim ini mengatur kalmodulinNa+/Ca++-exchanger (3Na+/1Ca++): mek utama utk mengeluarkan Ca++ miokardium; laju efluks Ca++
tergantung gradien Na+ yg merentas plasmalema
Struktur molekul intrasel yang terlibat mengatur Ca++ sitoplasmikStruktur mol –SR: tapak intrasel penting utk sekuesterisasi dan rilis cepat Ca++
Cenel rilis Ca++: sensitif thd IP3, Ca++, dan ryanodinPompa (Ca++-ATPase): bertanggung jawab untuk reseskuerisasi Ca++
Struktur molekul mitokondria, resorvoar pertukaran lambatCa++-uniporterElectroneutral Na+/Ca++ exchanger
Tapak Tindakan CaCBCaCB berikatan dgn cenel L-type (slow channels) yg banyak terdapat pd otot jantung dan otot polos (ada yg selektif di jtg ada pula di otot polos pemb drh) Kelas CaCB tipe L memp tapak yg berbeda dgn subunit 1
merup sub unit utama cenel ca++ (subunit 2, , , b juga
terdapat).
1
2
b
SSSubunit composition of L-type Ca2+ channel
• L-type (long-lasting)-excitation/contraction coupling of cardiac myocytes (nifedipine, verapamil, diltiazem)
• T-type (transient) - participate in pace making, highly expressed in sinusal cells (mibefradil)
• N-, P-type - expressed in neurons, are not affected by Ca2+
antagonists
III IV
II IIVIII
56 5
6
Out
In
I II III IV
The 1C subunit of the L-type Ca2+ channel is the pore-forming subunit
NH3+
NH3+
COO-
COO-
b
a1C
NH3+ COO-
a2
I II III IV
COO-
NH3+
d
The expression and function of the 1C subunit is modulated by other smaller subunits
L-Type Ca2+ Channel
The Three Classes of CCBs Bind to Different Sites
1,4-Dihydropyridines
(nifedipine)
Phenylalkylamines(verapamil)
Benzothiazepines(diltiazem)
Ca2+
pore
-
- -
-++-
Calmodulin
Ca2+ channels blockers
Ca2+ channels
Ca2+ (intracellular)
Ca2+ - calmodulin complex
MLCK
Myosin light chain PMyosin-actin interaction
Contraction
Control of smooth muscle contraction and the site of action of calcium
channel-blocking drugs
Increase the time that Ca2+ channels are closed
Relaxation of the arterial smooth muscle but notmuch effect on venous smooth muscle
Significant reduction in afterload but not preload
CCBs – Mechanisms of Action
The different binding sites of CCBs result in differing pharmacological effects
Voltage-dependent binding (targets smooth muscle)
Use-dependent binding (targets cardiac cells)
Cellmembrane
1
out
in b
+20
-80mV 2
DiltiazemVerapamil
1
b
1
out
in
+20
-80-30 2
1
Nifedipine
CellmembranemV
Outline
Introduction
CCB binding sites
Heterogeneity of action
Cardiac & hemodynamic
differentiation
Pharmacokinetics
Adverse effects
Contraindications
Summary
Why Do CCBs Act Selectively on Cardiac and Vascular Muscle?
N-type and P-type Ca2+ channels mediate neurotransmitter release in neurons
postsynaptic cell
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
MyofibrilPlasmamembrane
Transverse tubule
Terminal cisterna ofSR
Tubules ofSR
TriadTSR
Skeletal muscle relies on intracellularCa2+ for contraction
Cardiac cells rely on L-type Ca2+ channels for contractionand for the upstroke of the AP in slow response cells
Contractile Cells(atria, ventricle)
L-Type
Ca2+
Ca2+ Ca2+
Slow Response Cells(SA node, AV node)
L-Type
Ca2+
Ca2+
Vascular smooth muscle relies on Ca2+ influxthrough L-type Ca2+ channels for contraction
(graded, Ca2+ dependentcontraction)
L-Type
Ca2+
CCBs Act Selectively on Cardiovascular Tissues
Neurons rely on N-and P-type Ca2+ channels
Skeletal muscle relies primarily on [Ca]i
Cardiac muscle requires Ca2+ influx throughL-type Ca2+ channels
- contraction (fast response cells)- upstroke of AP (slow response cells)
Vascular smooth muscle requires Ca2+ influx
through L-type Ca2+ channels for contraction
Outline
Introduction
CCB binding sites
Heterogeneity of action
Cardiac & hemodynamic
differentiation
Pharmacokinetics
Adverse effects
Contraindications
Summary
The different binding sites of CCBs result in differing pharmacological effects
Voltage-dependent binding (targets smooth muscle)
Use-dependent binding (targets cardiac cells)
Cellmembrane
1
out
in b
+20
-80mV 2
DiltiazemVerapamil
1
b
1
out
in
+20
-80-30 2
1
Nifedipine
CellmembranemV
Differential effects of different CCBs on CV cells
AV
SN
AV
SN
Potential reflexincrease inHR, myocardialcontractilityand O2 demand
CoronaryVD
Dihydropyridines: Selective vasodilators Non -dihydropyridines: equipotent forcardiac tissue and vasculature
Heart ratemoderating
Peripheraland coronaryvasodilation
Reducedinotropism
Peripheralvasodilation
Effect Verapamil Diltiazem Nifedipine
Peripheralvasodilatation
Coronaryvasodilatation
Preload 0 0 0/
Afterload
Contractility 0/ / *
Heart rate 0/ /0
AV conduction 0
Hemodynamic Effects of CCBs
Outline
Introduction
CCB binding sites
Heterogeneity of action
Cardiac & hemodynamic
differentiation
Pharmacokinetics
Adverse effects
Contraindications
Summary
AgentOral
Absorption(%)
Bioavail-Ability
(%)
ProteinBound
(%)
Elimination Half-Life
(h)
Verapamil >90 10-35 83-92 2.8-6.3*
Diltiazem >90 41-67 77-80 3.5-7
Nifedipine >90 45-86 92-98 1.9-5.8
Nicardipine -100 35 >95 2-4
Isradipine >90 15-24 >95 8-9
Felodipine -100 20 >99 11-16
Amlodipine >90 64-90 97-99 30-50
CCBs: Pharmacokinetics
Calcium Antagonists
Mechanisms of Action
• reduce the transmembrane calcium transport (L-, T-, or N-type channels)
• alter myocardial oxygen supply and demand
– dilate epicardial coronary arteries
– reduce cardiac contractility
• nifedipine >> amlodipine and felodipine
– decrease heart rate
• verapamil and diltiazem (heart rate-modulating calcium antagonists) can slow the sinus node and reduce AV conduction
– reduce systemic vascular resistance and arterial pressure
Outline
Introduction
CCB binding sites
Heterogeneity of action
Cardiac & hemodynamic
differentiation
Pharmacokinetics
Adverse effects
Contraindications
Summary
Diltiazem Verapamil Dihydropyridines
Overall 0-3% 10-14% 9-39%
Hypotension ++ ++ +++
Headaches 0 + +++
Peripheral Edema ++ ++ +++
Constipation 0 ++ 0
CHF (Worsen) 0 + 0
AV block + ++ 0
Caution w/beta blockers + ++ 0
Comparative Adverse Effects
heart rate
blood pressure
anginal symptoms
signs of CHF
adverse effects
CCBs - Monitoring
Outline
Introduction
CCB binding sites
Heterogeneity of action
Cardiac & hemodynamic
differentiation
Pharmacokinetics
Adverse effects
Contraindications
Summary
Calcium Antagonists
• Contraindications
– overt decompensated heart failure - although amlodipine / felodipine are tolerated by patients with reduced LV ejection fraction
– Bradycardia, sinus node dysfunction, and AV nodal block
– long QT interval (contraindication for the use of mibefradil and bepridil)
• Side Effects
– hypotension, depression of cardiac function and worsening heart failure
– peripheral edema and constipation
– headache, flushing, dizziness and nonspecific central nervous system symptoms
– bradycardia, AV dissociation, AV block, and sinus node dysfunction
– Bepridil can induce polymorphous VT associated with prolonged QT interval
Contraindication Verapamil Nifedipine Diltiazem
Hypotension + ++ +
Sinus bradycardia + 0 +
AV conduction defects
++ 0 ++
Severe cardiac failure ++ + +
Contradications for CCBs
Outline
Introduction
CCB binding sites
Heterogeneity of action
Cardiac & hemodynamic
differentiation
Pharmacokinetics
Adverse effects
Contraindications
Summary
Indications
Hypertension
CCB’s effectiveness in the treatment of hypertension is related to a decrease in peripheral resistance accompanied by increases in cardiac index.CCB are also useful in the treatment of hypertensive patients with comorbidities such as: asthma, diabetes, angina, ond or peripheral vascular disease.
Angina pectoris
Calcium channel blockers act as coronary vasodilators, producing variable and dose-dependent reductions in myocardial oxygen demand, contractility, and arterial pressure. These combined pharmacologic effects are advantageous and make these agents as effective as beta blockers in the treatment of angina pectoris. They are indicated when beta blockers are contraindicated, poorly tolerated, or ineffective.In the presence of heart failure, the use of calcium channel blockers can cause further worsening of heart failure as a result of their negative inotropic effect.
Supraventricular tachyarrhythmias
Which CCB is most likely to cause hypotension and reflex tachycardia?
A. Diltiazem
B. Nifedipine
C. Verapamil
Contraindications for CCBs include (choose all appropriate):
A. Supraventricular tachycardias
B. Hypotension
C. AV heart block
D. Hypertension
E. Congestive heart failure
CCBs may improve cardiac function by:
A. Reducing cardiac afterload
B. Increasing O2 supply
C. Decreasing cardiac preload
D. Normalizing heart rate in patients with
supraventricular tachycardias
Thank you!