ISCHAEMIC HEART
DISEASE (IHD)
TREATMENT
RISK FACTORS
• a) risk factors
atherogenezis
• (ED, lipidic nucleus,
proliferation)
• b) risk factors
thrombotic arterial
occlusion
• (plaque destabilization,
thrombotická occluson,
fibrinolysis)
•organic stenosis
•vasospastic stenosis
•- stabile AP
•vasospastic AP
•Stenosis and thrombus
•nonstable AP, MI
For LV coronary perfusion is
diastolic interval decisive
• LV coronary perfusion
•ml/min
systole
diastole
Increased coronary perfusion
during decreased heart frequency
• LV coronary perfusion
•ml/min
• systole
diastole
COMPLEX TREATMENT IHD:
• a) stop atherogenic progresion – plaque stabilization
– elimination of endotelial dysfunction
• b) avoid arterial thrombotic occlusion (or rapid
restoration of perfusion)
• c) decrease of myocardial ischemia
- improvement of flow through ischemic
myocardium
- decrease myocardial metabolic requirements
- optimalization of metabolic energy utilization
• d) prevention of arrythmia
• e) prevention of myocardial remodelation and
development of heart failure
Atherosclerotic plaque stabilization
• a) endothelial dysfunction adjustment
– (hypolipidemics, ACEI, estrogens,
prostanoids, argininem suplementation,
calcium chanels blockers)
• b) atherosclerotic plaque stabilization
– soft nucleus (diet, hypolipidemics statins)
Effect of antioxidants on plaque
• Clinical studies
– Secondary prevention  20 000 pacients
– vit. C, vit. E, -karoten, 5 year tratment
• No any effect on cardiovascular
mortality and morbidity
• Study HOPE (vitamine E)
– Secundary prevention 9 500 patients, 4-5 year
– No any effect on cardiovascular mortality and
morbidity
• Scavangeres have no effect
COMPLEX TREATMENT IHD:
• a) stop atherogenic progresion – plaque stabilization
– elimination of endotelial dysfunktion
• b) avoid arterial thrombotic occlusion (ev. rapid
restoration of perfuson)
• c) decrease of myocardial ischemia
- improvement of flow through ischemic
myocard
- decrease myocardial metabolic requirements
- optimalization of metabolic energy utilization
• d) prevention of arythmiaa
• e) prevention of myocardial remodelation and
development of heart failure
ANTIPLATELET TRIALIST COLLABORATION
CV-mortality, MI, strake
• studies
•
•
příh
ody
1176
•
•
popul
ace
27210
1916
•
9530
RRR ± SD
12 ± 6 %
24 ± 5 %
•
3
•
primární •
prev.
cerebrální •
•
2
0
1
1
1
1
1
2
2
0
2
8
5
1
3
1
0
8
9
•
po IM
•
2270
•
15529
24 ± 4 %
•
AIM
•
2783
•
18126
26 ± 4 %
•
AP
•
398
•
3450
39 ± 9 %
•
•
245
•
3057
•
CABG/P
TCA
ICHDK
•
444
•
3864
•
po DVT
•
67
•
4771
•
ostatní
•
283
•
3948
33 ± 13 %
25 ± 10 %
42 ± 19 %
44 ± 10 %
•
celkem
•
9789
•
90297
•
•
•
•
•
•
•
•
Antiplatelet vs control
Br Med J 1994
25 ± 2 %
0.0
0.5
1.0
effect 2p < 0.00001
1.5
2.0
DECREASE OF
MYOCARDIAL ISCHEMIA
NITRATES
and
NO DONORS
NITRATES
• Mechanism of action
• - metabolized in vessel wall (enzymes or nitrosothiol) to
NO (identical with EDRF), stimulation cGMP
• - smooth muscle dillatation (arteries, veins, but arterioles
very small)
• Clinical effectivity
• - dilatation of eccentric stenosis in epicardial arteries
• - prophylaxis and treatment of coronary spasm
• (increased tolerance, decreased number of angina,
no evidence for better prognosis)
• - veins dilatation (only short term effect)
• - high doses arteriolodilatation (hypotension)
NITRATES
Generick
names
• Nitroglycerin
(NTG, GTN)
Admin.
dose
• subling. • 0,3 – 0,6 mg
• transderm.
• • p.o.
• 2,5 – 19,5 mg
onset
duration
• 30 s
• 1h
• 1h
• 15 – 20
min
• 6 – 14 h
• 2–4h
• Isosorbitdinitrate • subling.
(ISDN)
• p.o.
• 2,5 – 10 mg
• 20 – 120 mg
• 1–2h
• 4–6h
• Isosorbit 5
mono- nitrate
(ISMN)
• 5 min
• 30
min
• 20 – 100 mg
• 30
min
• 8 – 12 h
• p.o.
NITRATES
treatment of myocardial ischemia –
equivalent to calcium channel blockers
Usually underdosed – not properly used high
dose galenic forms ISDN a ISMN
ISMN or ISDN – first line
GTN (nitroglycerine) – only exceptionally
NITRATES
Adverse reactions:
• - headache (frequently limits use)
• - hypotension (rarely)
• - suspision for increased oxidation stress in vessel wall
• Nitrates tolerance:
• - decreased vasodilatation after long lasting treatment
• - SH group depletion, decreased cGMP, activation of
contra-regulation
• - intermitent treatment (nitrate-free interval)
MOLSIDOMINE
•
•
•
•
•
•
Syndonimine group – NO donors
Same mechanism as nitrates – NO release
Prodrug
No need for SH-group, without tolerance
onset
20 – 40 min
lasting
4–6h
8 – 12 h retard form
• dilatation smooth muscle in stenotic region
• Fibrinolysis activation (not clear effect)
• Indication:
prophylaxis AP
combination with nitrates
CALCIUM CHANNELS
BLOCKERS
CCB
Calcium channel blockers
• - effective for myocardial ischemia
(better quality of live)
• - short acting (nifedipine) worsening
patients prognosis
• - long lasting – slow down atherogenesis
and probably better prognosis
• - antihypertensive effect and
antiarythmic effect
CCB groups
• I. generation: low vascular selectivity
short time effect
•
(nifedipine, verapamile, diltiazem)
• II. generation: high vascular selectivity
•
long lasting effect
(felo-, isra-, niso-, nitre-, nilva-, nimodipin)
• III. generation:
high affinity to cell membranes
slow onset, long lasting effect
antiatherogenic effect
(amlo-, barni-, laci-, lercainidipin)
Pharmacodynamic effect of CCB
dihydropyridines
Selective vasodilatation
non - dihydropyridines
Myocardial depresiom
•peripheral
•vasodilatacion
peripheral
vasodilatation
coronary
vasodilatation
heart
rate
•SN
•AV
impulse
•Coronary
•dilatation
propagation
Myocardial
contractility
Bioavailability CCB
60-65
amlodipin
9-15
lacidipin
17-33
isradipin SR
nitrendipin
10-20
nilvadipin
10-19
7-30
nicardipin
nisoldipin
4-8
nifedipin SR
45-68
verapamil SR
12-48
felodipin SR
12-16
diltiazem SR
30-40
0
5
10
15
20
25
30
35
40
45
50
55
60
Bioavailability %
65
70
Maximal plasma levels CCB
tmax
612
612
amlodipin
barnidipin
lacidipin
12
1-2
isradipin SR
nitrendipin
1-2
nilvadipin
1-2
nicardipin
1-2
nisoldipin
0.2-0.6
nifedipin SR
1-2
verapamil SR
2-4
felodipin SR
12
diltiazem SR
0
2
4
6
8
10
tmax h
12
14
Slow onset mechanism for CCB III
generation
Lipophilic compound
Terminal aminogroup
hydrophilic
amlodipin
combination hydro- and lipophterminal allowed interaction with
phospholipids layer of sarcolema (binding to
membranes)
Slow onset mechanism for CCB
III generation
- slow and stable decrease of BP,
no activation of contra-regulation
1) no limited antihypertensive effect
(no vasoconstriction and fluid retention)
2) no proarythmogenic effect and tachycardia
3) no metabolic effect
Plasma halflife CCB
35-50
amlodipin
7-16
lacidipin
9
isradipin SR
8
nitrendipin
nilvadipin
15-20
nicardipin
1-4
nisoldipin
6-19
nifedipin SR
3-6
verapamil SR
5-12
felodipin SR
20-25
diltiazem SR
4-9
0
5
10
15
20
25
30
35
40
t1/2 (h)
45
50
55
ADVANTAGES OF AMLODIPINE
LONG HALFLIFE
• minimal plasma level fluctuations during day
• T/P index – ratio between minimal and maximal
blood level
-FDA requirements : effect "trough" 2/3 of "peak"
- amlodipin T/P index 68%,
- lacidipin, felodipin ER, verapamil SR and
nifedipin GITS index 37-66%
safety limits for missing dose
FARMACODYNAMIC PROPERTIES OF
CCB
ANTIISCHEMIC EFFECT
direct vasodilatation
endothelial function improvement
• ANTIATHEROGENIC EFFECT
Prophylactic effect of CCB
1) Vessel wall relaxation at
excentric stenosis
2) Block vasoconstriction
induced by exercise
3) Coronary spasm block
(variant AP)
4) Decreased heart rate
- increased perfusion
- decreased metabolic
demand
( non-dihydropyridines)
CAPE II - MONOTERAPY
Stress ECG – increase time to ischemia
500
P < 0,05
sec.
475
amlodipin
450
diltiazem
425
400
control
treatment
missing dose
CAPE II:
monoterapy x combination
amlodipine + BB against diltiazem + nitrates
stress ECG
100
zm ě na proti vs tupním u vyš e tře ní (s e c.)
zm ě na proti vs tupním u vyš e tře ní (s e c.)
100
75
50
25
0
75
amlodipin
50
amlodipin
+ atenolol
diltiazem
25
0
total loading
time to ischemia
time toST
depression
amlodipine + BB
total loading
time to ischemia
time to ST
depression
diltiazem + ISMN
diltiazem
+ ISMN
PREVENT: unstable AP and invazive
interventions
unstable AP/
heart failure
Cumulative Event/
Procedure Rate (%)
30.0
revascularisation
30.0
25.0
25.0
placebo
20.0
35%
15.0
10.0
P=.01
5.0
placebo
20.0
amlodipin
43%
15.0
10.0
amlodipin
5.0
P=.001
0.0
0.0
0
6
12
18 24
month
Pitt et al. Circulation. 2000.
30 36
0
6
12
18 24
month
30 36
PREVENT: important CV events
30.0
25.0
placebo
31%
Cases (%)
20.0
P=.01
15.0
amlodipin
10.0
5.0
0.0
0
6
12
18
month
Pitt et al. Circulation. 2000.
24
30
36
Contraindications and AR
• Non-dihydropyridine CCB
• AR – bradycardia, negative innotropic effect,
hypotension, obstipation
• CI – srdeční selhání, převodní poruchy,
hypotenze
• Dihydropyridine CCB
• AR – frequent perimaleolar oedema,
hypotension, reflex tachykardia
• CI – only hypotension
ACE INHIBITORS
IHD ACE INHIBITORS
Significant improvement of prognosis for
secondary prevention - even for patients wih
normal LV functon (study HOPE, EUROPA)
Not clear - that improvement during
secondary prevention is due to ACE inhibition
or decreased BP only
STUDY HOPE
Primary endpoints
0.15
Primary end point: CV-death +
placebo
MI + stroke
- 23% ramipril
0.1
0.05
P<0.0003
0.0
0
500
1000
daysí
Dagenais et al, 2001
1500
2000
Yusuf S et al. NEJM 2000;342:154-160.
STUDY EUROPA
Primary endpoint - mortality + MI + resuscit.
14
placebo
12
- 20 %
10
perindopril
8 mg
8
6
4
p = 0,0003
2
0
0
1
2
Placebo cases per year - 2,4 %
3
4
5 Roky
Remme P et al., NEJM 2003
POTASSIUM CHANNELS
ACTIVATORS
NICORANDIL
CLINICAL EFFECTS
• antiangina effectiveness comparable to BB,
CCB and nitrates
• Alternative choice - BB a CCB when
contraindicated or side effects
• Combination with BB possible
additive effect for „preconditioning“
NICORANDIL - IONA Trial
y
ta
lm
or
ta
lit
y
nt
m
or
ta
lit
to
Lancet 2002;359:1269-75
nicorandil
- 21% - 15%
CV
•Primary end-point: CVmortality + nonfatal MI +
hospitalization for angina
attack
- 17%
oi
•Randomization nicorandil 10
mg b.i.d. → 20mg b.i.d vs.
placebo
placebo
-p
•follow up 1-3 y, ø 1,6 ± 0,5
18
16
14
12
10
8
6
4
2
0
pr
im
.e
nd
•5126 patients with CHD and
stable AP – optimal treatment
BETA-BLOCKERS
BETA-BLOCKER
CLINICAL EFFECTS
• negative innotropic effect:
– LV filling time – prolongation
– coronary bed perfusion - improvememt
• negative innotropic effect
• metabolic demand decreased
• BP decrease
• antiarrythmic properties
(increased fibrilation treshold)
BETA-BLOCKER
CLINICAL EFFECTS
•  blockade1 juxtaglomerular receptor →
renin production decreased
• Catecholamine release in CNS - decreased
• Antioxidand properties ??
• cytoprotektive efect – even at high
catecholamine level
• Apoptoses inhibition
Efekt ß-blockers
1) antiischemic effect (better myocardial
perfusion, decreased metabolic denand)
2) antiarrhytmic effect
3) inhibition of hyperactive regulations:
- catecholamine release
- renin-angiotensin-aldosteron activation
- apoptosis
ACUTE DEATH REDUCTION FOR MI
BETA-BLOCKERS (meta-analysis)
40 %
FAVORITS
BETAXOLOL, BISOPROLOL
•- high cardioselectivity without ISA, hydrofilic
- long halflife (15-20 hours)
- small biodegradation variability
METOPROLOL
•- high cardioselectivity without ISA, lipophilic
- short and variable halflive
- exelent clinical trials – widely used BB
SINUSE NODE INHIBITORS
(BRADINES)
If current inhibitors
(hyperpolarisation) bradycardia only
IVABRADIN
 heart rate
(min-1)
 work-load tolerance
N = 360
5
(s)
80
70
0
60
-5
-10
-15
placebo
2,5 mg
5 mg
10 mg
50
40
30
20
10
-20
0
Borer J.S. et al., Circulation 2003;107:817-23
IVABRADIN vs ATENOLOL
PRIMARY END-POINT – LOADING TIME
n
atenolol
ivabradine
better [95% CI]
non inf.
•
•
•
Iva 5 mg bid
vs ate 50 mg od
at M1
595
286
•
•
•
Iva 7.5 mg bid 300
vs ate 100 mg od 286
at M4
•
•
•
Iva 10 mg bid 298
vs ate 100 mg od 286
at M4
- 35 sec
P for
6.7 [-7.4; 20.8]
P <0.0001
10.3 [-8.3;
28.8]
P <0.0001
15.7 [-2.9;
34.3]
0
equivalent
P <0.0001
+ 35 sec
METABOLIC
MODULATORS
ENERGY OUTCOMES
OPTIMALIZATION
 During ischemia – (pH decrease) inhibition
of glycolysis
 FA ß-oxidation main source of energy
 switch from FA ß-oxidation to glycolysis by
trimetazidine or ranolazine
 15% increase macroergic phosphates
membrane stabilization
TRIMETAZIDINE
• Modulation (inhibition 3-KAT) during ischemic
shift to glycolysis
• Optimalization of energetic metabolism of
kardiomyocytes
• No change in hemodynamic
• Well tolerated
3-KAT = 3-ketoacyl-CoA thioláza
METABOLIC MODULATORS
mechanism of action
glucose
Anaerobic glycolysis
pyruvate dehydrogenase
pyruvate
Lactic acid
Fatty
acids
fosforylation
cycle
TRIMETAZIDINE
clinical effectiveness
• Combination with BB, CCB, nitrates
• Second choice therapy when BB or
CCB contraindicated
• Additional therapy for all patients with
non compensated stabile AP
RECOMENDED COMBINATIONS
•
•
•
•
beta-blockers
beta-blockers
beta-blockers
CCB
•
Triple-combination:
trimetazidine
•
Acute attack: CCB + nitrates
+
+
+
+
dihydropyridine CCB
ISMN
trimetazidine
trimetazidine
BB + CCB (DHP) +
COMPLEX TREATMENT IHD:
• a) stop atherogenic progresion – plaque stabilization
– elimination of endotelial dysfunktion
• b) avoid arterial thrombotic occlusion (ev. rapid
restoration of perfuson)
• c) decrease of myocardial ischemia
- improvement of flow through ischemic
myocard
- decrease myocardial metabolic requirements
- optimalization of metabolic energy utilization
• d) prevention of arythmiaa
• e) prevention of myocardial remodelation and
development of heart failure
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