FARMAKOLOGI DAN

TOKSIKOLOG II
Program Studi : Farmasi
Semester : IVA. IVB, DAN IVC
Kode MK : FKC- 292 (2 SKS)

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 FARMASI
UNIVERSITAS SUMATERA UTARA
MEDAN
2011
Urip Harahap - Farmakologi dan Toksikologi II
 Garis Besar Materi Kuliah
Pokok Basahan Dosen Penyaji
1. Farmakologi dan Toksikologi Antihipertensi Prof. Urip Harahap, Apt.
2. Farmakologi dan Toksikologi Diuretika
3. Farmakologi dan Toksikologi Antagonis Kalsium
4. Farmakologi Toksikologi Antiaritmia
5. Farmakologi dan Toksikologi Antingina
6. Farmakologi dan Toksikologi Analgetika -Antipiretika Drs. Rasmadin Muchtar, MS., Apt
7. Farmakologi dan Toksikologi Antiinflamasi
8. Farmakologi dan Toksikologi Antidiare
9. 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

Farmakologi dan Toksikologi
Antagonis Calcium

URIP HARAHAP

Urip Harahap - Farmakologi dan Toksikologi II

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
 Regulation of Ca2+ extrusion
Ca2+-ATPase
Ca2+ Na+ -driven Ca2+ antiport

Ca2+
2 mM
Na+
ATP ADP
100 nM
ATP ADP Ca2+-ATPase

Ca2+
Ca2+ Ca2+

Mitochondria
2+
Ca2+-binding
Ca -sequestering compartments proteins
Regulation of Ca2+ entry
Receptor-dependent Ca2+ entry

R
Gq

PLCb
IP3
DAG

Voltage-dependent Ca2+ channel Polarized

Closed
Depolarized

Open-inactive Open-active
Classification of agents
 Three Classes of CCBs

Chemical Type Chemical Names Brand Names

Phenylalkylamines verapamil Calan,

Calna SR,
Isoptin SR,
Verelan

Benzothiazepines diltiazem Cardizem CD,

Dilacor XR

1,4-Dihydropyridines Nifedipine Adalat CC,

Procardia XL

nicardipine Cardene
isradipine DynaCirc
felodipine Plendil
amlodipine Norvasc
 Three Classes of CCBs
H3C 0 H3C CH3 0 CH3
CH CH3

H3C 0 C CH2 CH2 CH2 N CH2 CH2 0 CH3

C N
Verapamil

NO2 CH3
S N CH2 CH2 N
0 0 CH3

H3C 0 C C 0 CH3
0 C CH3

H3C CH3 0
N 0
H
CH3
Nifedipine Diltiazem
Widespread use of CCBs
 Angina pectoris
 Hypertension
 Treatment of supraventricular
arrhythmias
- Atrial Flutter
- Atrial Fibrillation
- Paroxysmal SVT
 Drugs for migraine prophylaxis

 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.
 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.
 Peran kalsium pada otot jantung dan otot polos
 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 myosin
kontraksi
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.

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 operated
Voltage (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 CaCB
Stretch 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
kalmodulin
Na+/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++ sitoplasmik
Struktur mol –SR: tapak intrasel penting utk sekuesterisasi dan
rilis cepat Ca++
Cenel rilis Ca++: sensitif thd IP3, Ca++, dan ryanodin
Pompa (Ca++-ATPase): bertanggung jawab untuk
reseskuerisasi Ca++
Struktur molekul mitokondria, resorvoar pertukaran lambat
Ca++-uniporter
Electroneutral Na+/Ca++ exchanger
Tapak Tindakan CaCB
CaCB 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).
Subunit composition of L-type Ca2+ channel
SS
2

 1 

b
• 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
The 1C subunit of the L-type Ca2+ channel
is the pore-forming subunit

I II III IV

Out

In

6
5 5 III IV
III 6 IV
II I
The expression and function of the 1C subunit
is modulated by other smaller subunits

a1C a2
NH3+ COO-
I II III IV
NH3+

COO-
NH3+
d COO-

b
L-Type Ca2+ Channel
NH3+ COO-
The Three Classes of CCBs Bind to Different Sites

1,4-
Dihydropyridines
(nifedipine)

+ -
- +

Ca2+
- pore -

Phenylalkylamines Benzothiazepines
(verapamil) - (diltiazem)
 Control of smooth muscle contraction
and the site of action of calcium
channel-blocking drugs
Ca2+ channels
Ca2+ channels
blockers Ca2+ (intracellular)
Calmodulin

Ca2+ - calmodulin complex

MLCK

Myosin light chain

P
Myosin-actin interaction

Contraction
 CCBs – Mechanisms of Action

 Increase the time that Ca2+ channels are closed

 Relaxation of the arterial smooth muscle but not

much effect on venous smooth muscle

 Significant reduction in afterload but not preload

The different binding sites of CCBs result in differing
pharmacological effects

Use-dependent binding (targets cardiac cells)

+20 out
mV 
Cell 1 2
-80 membrane  1
in
b Diltiazem
Verapamil

Voltage-dependent binding (targets smooth muscle)

+20 out
-30 
Cell 2
 1
-80
mV membrane 1
in
b Nifedipine
 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

Ca2+

Ca2+ Ca2+

Ca2+
Ca2+

postsynaptic cell
Skeletal muscle relies on intracellular
Ca2+ for contraction

Myofibril
Plasma
membrane
Transverse
tubule

Terminal
cisterna of
SR T Triad
SR

Tubules of
SR
Cardiac cells rely on L-type Ca2+ channels for contraction
and for the upstroke of the AP in slow response cells

Ca2+ Ca2+

L-Type L-Type

Ca2+ Ca2+

Ca2+

Contractile Cells Slow Response Cells

(atria, ventricle) (SA node, AV node)
Vascular smooth muscle relies on Ca2+ influx
through L-type Ca2+ channels for contraction

Ca2+

L-Type

(graded, Ca2+ dependent

contraction)
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 through
L-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

Use-dependent binding (targets cardiac cells)

+20 out
mV 
Cell 1 2
-80 membrane  1
in
b Diltiazem
Verapamil

Voltage-dependent binding (targets smooth muscle)

+20 out
-30 
Cell 2
 1
-80
mV membrane 1
in
b Nifedipine
Differential effects of different CCBs on CV cells

Dihydropyridines: Selective vasodilators Non -dihydropyridines: equipotent for

cardiac tissue and vasculature

Peripheral Heart rate

vasodilation moderating

Peripheral
SN
and coronary
AV
vasodilation
Potential reflex Coronary
increase in SN VD
HR, myocardial AV
contractility Reduced
and O2 demand inotropism
 Hemodynamic Effects of CCBs

Effect Verapamil Diltiazem Nifedipine

Peripheral
  
vasodilatation
Coronary
  
vasodilatation

Preload 0 0 0/

Afterload   

Contractility  0/ / *

Heart rate 0/  /0

AV conduction   0
 Outline

 Introduction
 CCB binding sites
 Heterogeneity of action
 Cardiac & hemodynamic
differentiation
 Pharmacokinetics
 Adverse effects
 Contraindications
 Summary
 CCBs: Pharmacokinetics

Oral Bioavail- Protein Elimination

Agent Absorption Ability Bound 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

-100
Nicardipine 35 >95 2-4
>90
Isradipine 15-24 >95 8-9
-100
Felodipine 20 >99 11-16
>90
Amlodipine 64-90 97-99 30-50
 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
 Comparative Adverse Effects

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
+ ++ 0
blockers
CCBs - Monitoring

 heart rate
 blood pressure
 anginal symptoms
 signs of CHF
 adverse effects
 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
 Contradications for CCBs

Contraindication Verapamil Nifedipine Diltiazem

Hypotension + ++ +

Sinus
+ 0 +
bradycardia

AV conduction
++ 0 ++
defects

Severe cardiac
++ + +
failure
 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!