Treatment of myocardial
ischemia
- CCB, nitrates, bradines,
metabolic treatment
Prof. MUDr. Jan Bultas, CSc.
and PharmDr. Pavel Jeřábek
2013
Causes of perfusion
disturbances
organic stenosis
- stabile AP
vasospastic component
vasospastic AP
growing thrombus
unstable AP, HA
Differences in coronary
circulation
• perfusion of the left ventricular myocardium
(unlike all other organs) in diastole
• reached maximum arteriovenous difference no reserve in oxygen extraction
• small functional reserve - mild ischemia leads to
failure of contractility
• great demands on the range of perfusion (rest x
load)
For LV coronary perfusion is
critical duration of diastole
Coronary flow LV
ml/min
systole diastole
systola diastola
The increase in coronary perfusion
by slowing the heart rate
Coronary flow LV
ml/min
systole
diastole
70% of coronary stenosis are eccentric
ENDOTHELIAL DYSFUNCTION
SMOKING
HYPERTENSION
DIABETES
INFECTION
DYSLIPIDEMIA
AGE
ENDOTHELIA
OXID.
 MACROPHAGES
OXID. LDL
INFILTRATION LIP.
STRESS
 PROLIFERATION
PROCOAGULATION
VASOCONSTRICTION
ATEROGENESIS
Arteria remodeling
PROGRESSION
compensatory enlargement of
the artery keep lumen untapered
normal
artery
exhaustion of compensatory
expansion - stenoses
The principle of intravascular ultrasound
examination (IVUS)
Angiography vs. IVUS
Angiography vs. IVUS
- most of atherosclerotic plaque in the
coronary bed don`t limit coronary perfusion
(are clinically silent), but can manifest by
rupture and thrombotic occlusion of arteries
- prophylaxis of ischemia improves quality
of life, but not the prognosis
Pathophysiology of myocardial ischemia
development
SUPPLY
CONSUMPTION
O2
• coronary stenosis,
spasm or thrombosis
• ↑ heart rate
•↓ perfussion pressure
(↓dBP)
• ↓ transp. capacity for O2
• ↑ heart rate
• ↑ contractility
• ↑ tension of LV wall
The consequences of myocardial
ischemia
• metabolic component
• mild hypoxia infarction without acid metabol.
retention starts glycolysis
• heavier perfusion defect leads to retention of
acid metabol., ↓pH suppresses glycolysis and
activates less energetically favorable βoxidation of FA
• electrophysiological component
• ion channels disorder, increasing intracelul.
Ca2 + → myocardium relaxation disorder,
reduced fibrilation threshold (arrhythmia)
Prophylaxis strategy of myocardial
ischemia
 coronary perfusion - revascularization
- relaxation in the place of
stenosis
- prolongation of diastole
- optim. diastol. BP
 myocard. consumpt. - optimal  rate
- optimal BP
- limitation of physical
activity
optim. of metabolism
- switch to glycolysis
INCREASE of the
coronary perfusion
Increase of the coronary perfusion
- relaxation at the stenosis
CCB (dihydropyridines, e.g. amlodipine, event.
verapamil, diltiazem)
nitrates (ISMN, ISDN, NTG, molsidomine, nebivolol)
Beware the pitfalls of vasodilation - arteriolodilatation may
lead to decreased blood pressure and catechol.
secretion or to steal phenomenon
- extension of the diastolic phase
-blockers (opt. cardioselect. with long T1/2)
CCB (verapamil type)
bradines (ivabradine - Procoralan®)
Principle of „ steal “ phenomenon
abolition of
autoregulation of flow
autoregulation by
behind stenosis
arterioloconstriction vasodilators
arteriolodilatation
behind stenosis
shift from the perfusion of ischemic areas to well perfused
Principle of „ steal “ phenomenon
- shift from the perfusion of ischemic areas to well perfused
after the arteriolodilator administration
autoregulation of blood flow
behind stenosis
abolition of autoregulation by
vasodilators
autoregulation of blood flow
behind stenosis unaffected
dilatation
dilatation
dilatation
arteriolokonstrikce
arteriolodilatace za
stenózou
dilatation
Tension control of vascular
smooth muscle
vasoconstriction
vasodilatation
NO
adrenergic
rec. α
Ca2+
cGMP
calcium channel L
K+
rec. AT1
potassium channel
Site of action of vascular
smooth muscle relaxing drugs
nitrates
NO donors
a -blockers
prazosin
terazosin,…
NTG, ISDN, ISMN
molsidomine
calc. channel blockers
NO
amlodipine,…
Ca2+
adren. rec. α
cGMP
calcium channel L
K+
rec. AT1
potassium channel
+- chnl.
activators
of
K
rec. antag. for AII (sartanes)
inhib. of conversion to AII (ACE-I) nicorandil
telmisartan,… perindopril, ramipril,…
CCB
- calcium channel blockers
Importance of calcium in cellular
communication and regulation
• INTRACELLULAR MESSENGER
- communication between cells
- regulation of important cell processes
• SYSTEM MAINTAINED BY ACTIVE
TRANSPORT MECHANISMS (calc. channels)
 maintained low concentration of ionized calcium
inside cells
• OVERSUPPLY OF CALCIUM LEADS TO
NECROSIS AND ARRHYTHMIAS
• e.g. after membrane damage or after prolonged
ischemia
Calcium channels in smth. vascular wall
muscle and in myocardium
(transfer of Ca via sarcolemma)
a) Channels controlled by the voltage change
- calc. channels of L type (long-term activation):
smth. vascular wall muscle and myocardium
- calc. channels of T type (temporary opening):
sinus node
b) Channels controlled by receptors
- in smth. muscle cells and vascular wall
- controlled by e.g. AII, sympat. stimulation of a1
Mechanism of L type channel
inhibition:
 lowering of ioniz. Ca2+ in myocytes of smth.
muscle
 decrease in calcium-calmodulin complex
formation (activates "myosin-light chain" kinasis,
enzyme that stimulates phosphorylation of light myosin
chain)
 bridges between actin and myosin are not formed
 inhibition of contraction
Mechanism of L type channel
inhibition:
the result of L type channel inhibition is:
- relaxation of smth. vascular wall muscle
- reduction of contractility
- slowdown of impulse formation and
conduction in ♥
Selectivity of L channel inhibition:
CCB acts in tissues:
1) with low intracellular calcium resources
(e.g. smooth vascular wall muscle)
lipophilic CCB (dihydropyridines)
hydrophilic CCB (diltiazem, verapamil)
2) where control of the action potential is
controlled by calcium (SA a AV node)
only hydrophylic CCB (diltiazem, verapamil)
Types and pharmacological effect of CCB
dihydropyridines
non -dihydropyridines
- selective vasodilatators
vasodilatation and cardiodepression
peripheral
vasodilatation
peripheral
vasodilatation
heart
rate
coronary
vasodilatation
SN
AV
heart
contractility
coronary
vasodilatation
ADVANTAGEOUS PHARMACOLOGICAL
PROPERTIES OF CCB
antiischemic effect
• dilatation of epic. parts of coronary
veins in stenosis + prevention of
spasms
antihypertensive effect
• arteriolodilatation (not always beneficial)
antiarrhytmic effect
• slowdown of impulse formation and
conduction in ♥
(verapamil and diltiazem only)
Ca channel blockers:
I. generation: lower vascular selectivity
short effect
(nifedipine, verapamil, diltiazem)
II. generation: high vascular selectivity
longer effect (felo-, isra-,
niso-, nitre-, nilva-, nimodipine)
III. generation: high affinity to cell membr.,
slow onset of action, long
effect (amlo-, barni-, laci-,
lercainidipine)
DILTIAZEM, VERAPAMIL
•
•
•
•
90% GIT absorption, variable BA
„first pass effect“ 20-70%
short bio- half-life, prolonged forms needed
inhibition CYP3A4 and P-gp – risk of
interactions – ↑ availability a ↓ degradation of
substrates
•
•
•
•
•
relaxation of epic. parts of cor. arteries
arteriolodilatation (↓ of peripheral resistance)
slowdown of impulse formation and conduction
negative inotropic effect ( contractility)
slowdown of intestinal motility (obstipation)
CCB - dihydropyridines
• advantages against I. generation:
• high vascular selectivity
• longer duration of action
• slower onset
•many representatives: amlo-, barni-,
felo-, isra-, laci-, lercaini-, niso-, nitre-,
nilva-, nimodipin
Differences in pharmacokinetic
properties
• differences in the speed of onset
(activation of regulatory mechanisms)
• differences in biological half-life
(fluctuation of effect during the day and if a
dose is missed)
COMPARISON OF THE SPEED OF MAXIM.
PLASMATIC LEVEL ACHIEVEMENT
612
612
amlodipine
barnidipine
lacidipine
12
1-2
isradipine SR
nitrendipine
1-2
nilvadipine
nicardipine
1-2
nisoldipine
1-2
nifedipine SR
0.2-0.6
verapamil SR
1-2
felodipine SR
2-4
diltiazem SR
0
122
4
6
8
10
12
effect onset tmax (hrs)
14
The advantages of the slow onset
of action (CCB III. generation)
- very slow and stable BP drop doesn‘t activate
regulatory mechanisms, main. sympatoadrenergic
advantages of minimal system stimulation
1) antihypertensive response is not limited
(by vasoconstriction and fluid retention)
2) proarrhythmogenic and tachycardic effect is not
involved
3) no metabolic effect (hyperlipidemic and
hyperglycaemic)
COMPARISON OF BIOLOGICAL HALF-LIFES
OF CCB
35-50
7-16
amlodipine
lacidipine
9
isradipine SR
8
nitrendipine
15-20
nilvadipine
1-4
nicardipine
nisoldipine
6-19
nifedipine SR
3-6
verapamil SR
5-12
felodipine SR
20-25
diltiazem SR
0
5
4-9
10
15
20
25
30
35
40
45
biological half-life t1/2 (hrs)
50
55
ADVANTAGES OF LONG BIOLOGICAL
HALF-LIFE
-
minimal fluctuation of antihypertensive
and antiischemic effect during the day
T/P index
- ratio btw. min. and max. antihypertensive effect
- FDA: effect "through" optimally 2/3 "peak„ effect
sufficient effect even when a dose is missed
Differences of dihydropyridine CCB
• don‘t have negative chronotropic effect
• don‘t have negative dromotropic effect
• don‘t have negative inotropic effect
•
•
•
•
larger vascular selectivity
longer period of action
slower effect onset
don‘t inhibit CYP3A4
ADVANTAGEOUS
PHARMACOKINETIC PROPERTIES
OF AMLODIPINE
 high bioavailability 60-65%
(predictible and stable effect)
 slow onset of action - tmax 6-12 hrs
- high lipofility with penetration to the lipid bilayer
(doesn‘t activate regul. mechanisms)
 very long bio- half-life 35-50 hrs
(minimal effect fluctuations when missed dose)
 possible use in gravidity or by heart failure
INDICATION OF CCB
Non-dihydropyridine CCB
• prophylaxis and atrial arrhythmya treatment
slowdown of conversion from atrial to
ventricular in atrial fibrillation, ev. prophylaxis
of atrial extrasystoles
• hypertension treatment
• prophylaxis of stenocardia
Dihydropyridine CCB
• hypertension treatment (also in gravidity)
• prophylaxis of stenocardia
CI and AE of CCB
Non-dihydropyridine CCB
AE – bradycardia, conduction abnormalities, ↓
contractility, hypotension, obstipation
CI – heart failure, conduction disturbances,
hypotension
Dihydropyridine CCB
AE – frequent perimalleolar edema,
rarely hypotension, refl. tachycardia
CI – hypotension
NITRATES
NITRATES mechanism of
action
inhibition of
adhesion
and activation of
neutrophils
inhibition of adhesion
and activation of
thrombocytes
NO
Inhibition of
vasoadhesive molecules
expression
enzyme effect
modification by
nitrosylation
oxidative stress
control
vasodilatation
inhibition of smooth muscle
migration and proliferation
NITRATES mechanism of action
NO donors
ISDN
ISMN
NTG
vasodilatation
NITRATES mechanism of action
NO
-SH not necessary
donors
ISDN
ISMN
free –SH necessary for the effect
NTG
vasodilatation
NITRATES
mechanism of action
• metabolise in vascular wall to NO - stimulation
cGMP
• dilatation of smth. muscle cells
(arteries, veins, less arterioles)
clinical effect
• relaxation of eccentric stenoses of epicardial art.
• prophylaxis and treatment of coronary spasms
(improved load tolerance, less AP incidence)
• venodilatation (minor clinical significance)
• arteriolodilatation (only high doses)
NITRATES – tolerance induction
tolerance -  therapeutic response (less
vasodilatation) after prolonged exposure (days)
cross tolerance NTG and ISDN / ISMN
mechanism:
- depletion of -SH grps. (donor is glutathion)
-  vasodilat. response to cGMP (tachyphylaxis)
prevention: asymmetric administration
(during stress only, without night dose)
transition to molsidomine or CCB
NITROGLYCERIN
• very fast onset, but short duration of action
• suitable only for stenocardia treatment (optim.
spray)
ISDN (isosorbide dinitrate):
• actively metabolised to ISMN
• short-term (min), qiuck onset (sec)
• indicated for the prophylaxis and treatment of
stenocardia in AP
ISMN (isosorbide mononitrate):
• long-term effect (6-12 hrs.), slow onset
• indicated for the prophylaxis and treatment of
stenocardia in AP
Molsidomine
• direct NO donor,  tolerance risk
• only for ischemia prophylaxis
Transformation of ISDN to 5-ISMN
oral administration of ISDN
sublingual. admin of ISDN
NITRATES
• in the treatment of myocardial ischemia
substituted by CCB because of reliable
effect and favorable influence to the
incidence of CV diseases
• nitrates don‘t influence the development or
prognosis of CV diseases
• trend to molsidomine, ISMN, ev. ISDN
• shift from nitroglycerin
• valuable in the treatment of stenocardia
(spray, s.l.) – only nitroglycerin and ISDN
CCB or nitrates ?
CCB
• longer effect
• no tolerance develop.
• probably a positive
impact on prognosis
• more reliable
• antihypertenzní ef.
• potentiation of statins
• effect on arterioles
(steal ef.,  periph. resistence)
NITRATES
• very fast onset
• effect mainly on the
epic. part of
bloodstream
(don‘t induce steal ef.)
• short effect
• tolerance devel.
Betablockers
- rational therapeutic procedure in the
treatment of myocardial ischemia
(optimally in combination with
coronary vasorelaxant)
BENEFITS OF -BLOCKERS
• negatively chronotropic effect:
– prolongation of left ventricular filling
time
– improvement of the coronary perfusion
• negatively inotropic effect
- ↓ metabolic demands
• decrease of blood pressure
• antiarrhytmic properties
- ↑ fibrilation threshold
BRADINES - inhib. of sinus node
inhibitores of If current
(hyperpolarisation)
without additional effect
IVABRADINE
ivabradin
RR
0 mV
-40 mV
-70 mV
•
•
•
•
decrease heart rate ONLY
maintaines myocardial function
no proarrhythmogenic effect
well tolerated (even in risk patients)
IVABRADINE
• effect comparable with βblockers, but less AE
5
0
placebo
2,5 mg
5 mg
10 mg
-5
• indications – ↓ heart rate if BB
alone or in combination is
contraindicated
-10
-15
-20
 HEART RATE
(min-1)
METABOLIC
MODULATORS
OPTIMALISATION OF ENERGY
UTILIZATION IN ISCHEMIC
MYOCARDIUM
• under conditions of severe myocardial ischemia
(decrease in pH), energy-favorable glycolysis is
reduced and energy is obtained
disadvantageously by ß-oxidation of FA
• shift from ß-oxidation of FA to glycolysis by the
administration of trimetazidine =>
+15% macroergic phosphates
Effect of myocardial metabolism modulators
glucose
pyruvate
fatty
acids
Krebs
cycle
oxidative
phosphorylation
TRIMETAZIDINE
• metabolic modulator (3-ketoacyl-CoA thiolase = 3-KAT)
• optimizes energetic cardiomyocyte metabolism
• hemodynamically neutral
• well tolerated
• relatively small antiischemic effect (max. tolerance by 1020%)
TRIMETAZIDINE – clinical use
• not the first choice, always after failure of
BB and CCB (or nitrates)
• additive or alternative therapy in patients
with AP, poorly controlled by BB
combined with vasodilators
• alternative to BB or CCB when
contraindications or intolerance
How do you increase coronary
perfusion???
CCB (dihydropyridines, opt. amlodipine, event. verapamil,
diltiazem)
nitrates (ISMN, ISDN, NTG, molsidomin, nebivolol)
Beware the pitfalls of vasodilation - arteriolodilatation may lead to
decreased blood pressure and catechol. secretion or to steal
phenomenon
- extension of
diastolic phase
-blockers (opt. cardioselect. with long effect duration)
CCB (verapamil type)
bradines (ivabradine)
The importance of the heart
rate for the myocardial load
The impact of the increased heart rate
- the reduction of diastole → deterioration of
coronary perfusion
- the increase of myocardial metabolic demands
The impact of the decreased heart rate
- extension of diastole → cor. perfusion improv.
- extension of diastole → increase in LV diastolic
filling → ↑ contractility → maintained ♥
output, metabol. demands don‘t drop
patients with AP
contraindication of β-bl-.
all
yes
no
beta-bloc.
verapamil, diltiazem
ASA
statin
CCB (amlodpine)
ACE inhibitor
short-term nitrate
still symptomatic?
increase dose of CCB or
add ISMN or molsidomine or trimetazidine
still symptomatic?
ivabradine
still symptomatic?
CABG, angioplasty
CABG, angioplasty
The strategy of care about patient with
IHD is a complex of precautions
Prophylaxis of ischemia is only one of many
procedures:
• prevention of thrombotic clot
• prevention of plaque destabilization and
slow down of atherogenesis
• prophylaxis of myocardial ischemia
• prevention of LV remodeling and failure
• prevention of arrhythmia development