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!