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 componentvasospastic AP

growing thrombusunstable 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

systola diastola

Cor

onar

y fl

ow L

V

ml/minsystole diastole

The increase in coronary perfusion by slowing the heart rate

systole diastole

Cor

onar

y fl

ow L

V

ml/min

70% of coronary stenosis are eccentric

ENDOTHELIAL DYSFUNCTION

ENDOTHELIA

SMOKING HYPERTENSION DYSLIPIDEMIA DIABETES INFECTION AGE

­ OXID. MACROPHAGES PROCOAGULATION

OXID. LDL INFILTRATION LIP. VASOCONSTRICTION

STRESS PROLIFERATION ATEROGENESIS

PROGRESSION

normalartery

exhaustion of compensatory expansion - stenoses

compensatory enlargement of the artery keep lumen untapered

Arteria remodeling

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

• coronary stenosis,   spasm or thrombosis• ↑ heart rate•↓ perfussion pressure (↓dBP)• ↓ transp. capacity for O2

• ↑ heart rate• ↑ contractility• ↑ tension of LV wall

SUPPLY CONSUMPTION

O2

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 β-oxidation 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 stenosisCCB (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

autoregulation of flow behind stenosis

abolition of autoregulation by vasodilators

shift from the perfusion of ischemic areas to well perfused

arterioloconstriction

arteriolodilatationbehind stenosis

Principle of „ steal “ phenomenon- shift from the perfusion of ischemic areas to well perfused

after the arteriolodilator administration

dilatation

dilatation

dilatation

dilatation

arteriolo-konstrikce arteriolo-

dilatace za stenózou

autoregulation of blood flow behind stenosis

abolition of autoregulation byvasodilatorsautoregulation of blood flow

behind stenosis unaffected

Tension control of vascular smooth muscle

K+

Ca2+

NO

cGMPadrenergic rec. α

rec. AT1 potassium channel

calcium channel L

vasoconstrictionvasodilatation

Site of action of vascular smooth muscle relaxing drugs

rec. antag. for AII (sartanes)inhib. of conversion to AII (ACE-I)

calc. channel blockers

activators of K+- chnl.

nitratesNO donors

NTG, ISDN, ISMN molsidominea -blockers

prazosinterazosin,…

K+

Ca2+

NO

nicorandil

cGMPadren. rec. α

rec. AT1 potassium channel

calcium channel L

amlodipine,…

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

1

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

AV

SN

coronaryvasodilatation

dihydropyridines- selective vasodilatators

non -dihydropyridines vasodilatation and cardiodepression

¯ heart rate

coronaryvasodilatation

peripheralvasodilatation

¯ heart contractility

peripheralvasodilatation

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)

0 2 4 6 8 10 12 14

diltiazem SR

felodipine SR

verapamil SR

nifedipine SR

nisoldipine

nicardipine

nilvadipine

nitrendipine

isradipine SR

lacidipine

barnidipine

amlodipine

COMPARISON OF THE SPEED OF MAXIM. PLASMATIC LEVEL ACHIEVEMENT

effect onset tmax (hrs)

6-126-12

1-2

1-2

1-2

1-2

1-2

1-2

1-2

0.2-0.6

2-4

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 stimulation1)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)

0 5 10 15 20 25 30 35 40 45 50 55

diltiazem SR

felodipine SR

verapamil SR

nifedipine SR

nisoldipine

nicardipine

nilvadipine

nitrendipine

isradipine SR

lacidipine

amlodipine

biological half-life t1/2 (hrs)

35-50

7-16

9

8

15-20

1-4

6-19

3-6

5-12

20-25

4-9

COMPARISON OF BIOLOGICAL HALF-LIFES OF CCB

ADVANTAGES OF LONG BIOLOGICAL HALF-LIFE

- minimal fluctuation of antihypertensive and antiischemic effect during the dayT/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 CCBNon-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 CCBNon-dihydropyridine CCB AE – bradycardia, conduction abnormalities, ↓

contractility, hypotension, obstipation

CI – heart failure, conduction disturbances, hypotension

Dihydropyridine CCBAE – frequent perimalleolar edema, rarely hypotension, refl. tachycardia

CI – hypotension

NITRATES

NITRATES mechanism of action

inhibition of adhesion

and activation of neutrophils

inhibition of adhesionand activation of

thrombocytes

Inhibition ofvasoadhesive molecules

expression

enzyme effect modification by

nitrosylation

oxidative stress control

vasodilatationinhibition of smooth muscle migration and proliferation

NO

NITRATES mechanism of action

ISDN ISMN

NO donors

NTG

vasodilatation

NITRATES mechanism of action

ISDN ISMN

NO

donors

NTG

vasodilatation

-SH not necessary

free –SH necessary for the effect

NITRATESmechanism 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 APISMN (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

• decrease heart rate ONLY• maintaines myocardial function• no proarrhythmogenic effect• well tolerated (even in risk patients)

RR

-70 mV

-40 mV

0 mV

ivabradin

IVABRADINE

-20

-15

-10

-5

0

5

placebo

2,5 mg

5 mg

10 mg

HEART RATE(min-1)

• effect comparable with β-blockers, but less AE

• indications – ↓ heart rate if BB alone or in combination is contraindicated

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

fatty acids

oxidative phosphorylation

pyruvate

Krebscycle

TRIMETAZIDINE• metabolic modulator (3-ketoacyl-CoA thiolase = 3-KAT)

• optimizes energetic cardiomyocyte metabolism

• hemodynamically neutral

• well tolerated

• relatively small antiischemic effect (max. tolerance by 10-

20%)

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

all contraindication of β-bl-.

ASAstatin

CCB (amlodpine)ACE inhibitor

short-term nitrate

yes no

beta-bloc.verapamil, diltiazem

still symptomatic?

increase dose of CCB oradd ISMN or molsidomine or trimetazidine

still symptomatic?

CABG, angioplastyivabradine

still symptomatic?

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