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2007

Minor differences in structure may have

huge impact on pharmacodynamics
of ACE inhibitors
ACE inhibitors can be divided in three categories into
those containing:
Sulfhydril group (benazepril, captopril, zofenopril)
Carboxyl group (cilazapril, enalapril, lisinopril,
perindopril, quinapril, ramipril, spirapril, trandolapril)
Phosphoryl group (fosinopril)
Most of the ACE inhibitors are prodrugs (except
captopril, lisinopril) that remain inactive until they
are converted into active metabolites.
ESC Expert consensus document. Eur Heart J 2004; 25: 1454-70.

Duration of Action
Dose-Response: Antihypertensive Effects
Trough-to-Peak (T:P) Ratios

Ang II
VSMC

Angiotensinogen

Renin
Aldosterone
(Adrenal/CV tissues)

Angiotensin I
ACE

Angiotensin II

McFarlane SI et al. Am

J Cardiol. 2003;91(suppl):30H7.

ACE-I :

Angiotensin I

Bradykinin
ACE/Kininase II

Angiotensin II
ACE inhibitors

Bradykinin

Angiotensin II

Oxidative stress
Endothelial dysfunction
Glucose metabolism
Plaque growth
Fibrous cap stability
MMP activity

Nitric oxide

MMP = matrix metalloprotease

Fleming I et al. Physiology. 2005;20:91-5.

 ( )

II-

M. Remko, Acidity, Lipophilicity, Soluility, Absorption and Polar Surface Area

of Some ACE Inhibitors, Chem. Pap. 2007, 61 (2): 133-141.



( )
-

10%

(/)
-
-
-
-
-
-
-

Dzau VJ. Arc Intern Med 1993;153

90%

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Ferrari R, Fox KM. Perindopril - a major contribution to the prevention and treatment of cardiovascular
disease. France: Wolters Kluwer Health; 2008.


/ /

-
II-

Nitric oxid (NO ) -

Ferarri R. Angiotensin-converting enzyme inhibition in cardiovascular disease: evidence with perindopril. Expert Rev Cardiovasc Ther 2005; 3:
1529.
Ceconi C et al. ACE inhibition with perindopril and endothelial function. Results of a substudy of the EUROPA study: PERTINENT.

 - .

,
,

20%-

14

12

Placebo

10
8
6

Perindopril
4
2

p = 0.00033

0
0

5 Years

Lancet 2003; 362: 7828.

ADVANCE 2--

+
(n=5569)

(n=5571)

Patel A. Lancet. 2007;370:829-840.

 +

A
from dilation
of resistant vessels and reduction of systemic
peripheral resistance, which gradually reduces
blood pressure.

-
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.

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5 ,
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8

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H 20
(20 /12.5 HCTZ)

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/25 HCTZ)
A H (2.5
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o-
2 /0.625 ,
4 /1.25 ,
8 /2.5

A ()
.

2007 E/E-
, a II

(A
.

2007 E/E-

Mancia G. et al. Guidelines for the Management of Arterial Hypertension. J Hypertension 2007. Mancia G, et al.
Reappraisal of guidelines on hypertension management: a European Society of Hypertension Task Force document.
J Hypertension 2009.

o // ?
A

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risk reduction (%)

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-15

-13

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-25
-30

-25

-25

ae

13%, 25%- .
25%- .
ae .

Dahlof B, et al. Lancet. 2002;359:995-1003. The purpose of the Losartan Intervention For Endpoint reduction (LIFE)

o
.
2-

1513
3-4
.
reduced the risk of the composite primary endpoint (doubling of serum
creatinine, end stage renal disease and death) by 16% compared with placebo.

25%- 2
.
28%-
.
NEJM, 2001. 345: 861-69. The purpose of the Reduction of Endpoints in Non insulin dependent
diabetes mellitus with Angiotensin II Antagonist Losartan (RENAAL)

32% .
NEJM, 2001. 345: 861-69.

o 1
24 . . .

-

.

Circ Res. 2002;90:770-776.

Hypertension. 2002;40:521-527.
Clin Pharmacol Ther 2002; 72:302-7

2007 E/E-
(A)
.

,
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,
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,
,

Diuretics are classified

according to the site of action

Their common property is the natriuretic effect, followed by fluid

reduction in the body.

1.5 -
-

,
,

.

(, )

(TOMHS
)

J Hypertension; 2001

2.5 ( ) 1.5 ( ) .

2
.
Leonetti G. Clinical positioning of indapamide sustained release 1.5 mg in management protocols for
hypertension. Drugs 2000; 59 (Suppl. 2): 27-38.

 1,5
2,5 -
62,5% -
.


1 1.5
.
:
,
,
- .

2007 Guidelines for the management of arterial hypertension, EHJ 2007;28:1462-1536 Reappraisal of European guidelines on
hypertension management. J Hypertens. 2009 ; 27 (11): 2121-58.

CCB: reduction of contractility and

conductivity in the heart, vasodilatation
contractility of

Endothelium
dependant
vasodilation

vascular and heart

muscle cells
Block of flux of
Ca+ ions into
cells
Oxygen
CCBs
NO
demand in
release
myocardium

Antiatherosclerotic
Anti-thrombotic
effect
Haria M, Wagstaff AJ. Drugs 1995:50 (3)560-86

Amlodipine: 3rd generation CCB

Second generation
Group

Dihydropyridines

First
generation

Novel
Pharmaceutical
forms

nifedipine
nicardipine

nifedipine SR
felodipine ER
nicardipine SR

diltiazem

diltiazem SR

verapamil

verapamil SR

NCE

isradipine
Nimodipine
Nitrendipine

Benzothiazepines

Phenylalkylamines

Lscher TF, Cosentrino F. Drugs 1998; 55(4):509-17

gallopamil

Third
generation

amlodipine
lacidipine

 5 , 10

464 4427
:

23 28%- .
- 4.5%- .
22%- .
- .
.
.

: Te ,

, , .

Vrablk M, Freiberger T, Lnsk V, eka R. The Atractiv project: improved cardiovascular

prevention in the context of primary care in the Czech Republic. Vnit Lk 2008; 54: 871-9.

 + :
ETNA and ETNA +
1000
16
:

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- .
- .
Te , .
Te
.

:


.

1. .., ... . 2007; 1: 30-2.

2. .., ...
( ). 2008; 2: 35-9.

47 .

Data on file, Krka, d. d., Novo mesto, Slovenia, 2009.

Kka AA
25

Kka
Kka AA

25

2000 Launch of
Lorista/Lavestra
(losartan)

2002 Krkas enalapril the

first enalapril with the
European Pharmacopoeia
certificate of suitability

1988
Launch of
Enap
(enalapril)

1988

1994

2000

2002

2004 Launch of
Ampril/Amprilan
(ramipril)
1994 Patent protection for
enalapril maleate tablet
pharmaceutical formulation and
chemical synthesis

2004

2006 Launch of
Valsacor (valsartan)

2005

2005 Launch of
Prenessa/Perineva
(perindopril)

2006

2007

2008

2007 Golden Otis for

innovative solutions
relating to perindopril

2008 Publication
of an international
clinical study of
Lorista/Lavestra

Kka

2010 Launch of
Karbis (candesartan)

Kka AA

25

2010 Launch of
2012 Platinum
Tolura (telmisartan) Ounce for launch
of
2010 Launch of
Prenessa/Perineva
Ifirmasta/Irabel
in Russia
(irbesartan)
2010 Launch
of Olimestra
(olmesartan)

2009

2010

2011

2012

2010 5th
anniversary of
Prenessa launch

2009 Publication of
ATRACTIVE study

2011 Launch of
Amlessa/Dalnessa
(perindopril/amlodipine)

2013
2012 Publication
of LAURA study
of Lorista/Lavestra
2012 Publication
of Valsacor study
on erectile
dysfunction

What differentiate us from others?

Krkas
medicines
acting on RAAS


.
From one important award

to global recognition of
quality in the world

Gaining experience through

continuous re-evaluation
From bioequivalent
studies

to numerous international
clinical trials

Following the latest guidelines in the treatment

of hypertension and offering the most up-to-date
medicines
From golden standard in the
treatment of hypertension

to the widest portfolio of

medicines acting on RAAS

Krkas
medicines
acting on
RAAS

K
,
RAAS Renin Angiotenzine Aldosterone System
Source: IMS, Intellix, Medicube, Pharmexpert, Pharmstandart, Pharmazoom 1-6 2012, est 2012, TM 20

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.
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.