Summary of general pharmacotherapeutic

approaches in cardiology

Jan Bultas, Debora Karetová 2013

Topics

• heart rate and conduction intervention

• blood pressure intervention

• myocardial ischemia intervention

• myocardial contractility intervention

• fluid retention intervention

• hyperactivated hemostasis intervention

• dyslipidemia intervention

Heart rate and conduction

chronotropy

dromotropy

Heart rate interventionheart rate acceleration •sinus node: muscarine rec. inhibition (atropine) or β1 adrenergic receptor activation (xamoterol or isoprenaline)•cardiostimulation

heart rate slowdown•β1 adrenergic receptor inhibition (betablockers)•sinus node specific iont channels inhibition (slowdown of sinus node pacemacker cells spontanneous depolarisation)

Importance of heart rate slowdown

• coronary flow rate improvement due to diastolic phase prolongation

• metabolic myocardial demand reduction

• correlation of heart rate and prognosis

calciumL channel

potassium channel Ik

natrio-potassium channel If

Sinus rhythm - rate control

parasympatheticmuscarine rec.

adrenergic 1 receptor

calciumT channel

calciumL channel

potassium channel Ik

natrio-potassium channel If

Sinus rhythm - rate control

parasysympath.muscarine rec.

adrenergic 1 receptor

calciumT channel

atropine -blockers

CCB /verapamil/bradins – If channel inhib.

.

Benetos A et al. Hypertension 1999;33:44-52

Relation of heart rate and total and cardiovascular mortality in males and females in the course of 20 yrs of follow-up

Pharmacology of heart rate slowdown

• β1 adrenergic stimulation inhib. (β blockers)

- heart rate reduction by 10-20 beats/min

• Na/K channel If inhibition (bradins, ivabradine)

- heart rate reduction by 10-20 beats/min• calcium L type channel inhib. (verapamil)

- heart rate reduction by only ≈5 beats/min

Better is β blocker and bradin combination than β blocker and verapamil (due to negative AV

conduction effect)

Relation of mortality reduction and heart rate slowdown with -blocker therapy in secondary prevention

pindolol

oxprenolol

practolol

mo

rtal

ity

re

du

ctio

n (

%)

heart rate slowdown (beats/min)

timolol

metoprolol

propanololpropanolol

0

50

100

150

200

250

70 až <72 72 až <75 75 až <80 80 až <87 ≥87

SHIFT, Bohm M et al. Lancet 2010

115%133%

180%

234%

100%

heart rate CV

mo

rtal

ity

and

ho

spit

alis

atio

n d

ue

to h

eart

fai

lure

(%)

%

ns

P=0,027

P<0,001

P<0,001

Relation of CV mortality to heart rate (in quintiles of heart rate) – chronic HF

Atrio-ventricular conduction deceleration

• slowdown of ventricular rate in atrial fibrilation

• tachyarrhytmia treatment

Atrio-ventricular conduction deceleration strategy - β1 adrenerg. activity inhibition (β1 -blockers)

- parasympatic activity stimulation (digoxin)

- ion channel inhibition- Ca2+ (verapamil) - Na+ (propafenone,..) - K+ (amiodarone,…)

I. cl. IV. cl.

III. cl.I. cl.

digoxin

Antiarrhythmics in atrial fibrillation - sinus node rhythm restauration

propafenone flecainide sotalol

amiodarone

contraindic.in left ventricle failure

failure of other antiarhythmics orheart failure

Antiarrhythmics in atrial fibrillation - reduction of ventricle rate by atrio-ventricular conduction deceleration

• betablockers• verapamil, diltiazem • digoxin (vagus activation)

combination of antiarrhytmics to reach the ventricle rate <90/min

Antihypertensive therapy

Blood pressure

- arterial hypertension – common status (≈ 1/3 population), important risk factor of CV diseases (stroke, CHD,…) with negative prognostic effect

- habitual arterial hypotension – rare status deteriorating life quality with no prognostic impact

Hypertension prevalence according to age

Kearney et al. Lancet 2005;365:21723

14,421,2

32,6

44,8

60,3

71,2

6,29,9

23,3

42,0

61,3

80,3

0

20

40

60

80

100males females

hyp

erte

nsi

on

pre

vale

nce

(%

)

2029 703039 4049 5059 6069 age

CV

mo

rtal

ity

0

2

4

8

115/75 135/85 155/95 175/105

6

syst. BP/diast. BP (mmHg)

*Individuals aged 40–69 years

4x risk

CV mortality doubles with BP increase by 20/10 mmHg

Lewington et al. Lancet 2002;360:1903–13

1x risk

2x risk

8x risk

Strategy for the treatment of hypertension

• blockade of hyperactivated regulatory mechanisms

– ACE-I, ARBs, aldosterone rec. blockers,

– - or α+-blockers

• peripheral resistance decrease

– calcium channel blockers, central + peripheral

vazodilatators, ACE-I, ARBs, α-blockers

• reduction of circulating fluid volum

– diuretics

• reduction of hyperkinetic circulation

– - or α+-blockers

BP normalisation / optimalisation

- vascular wall damage risk reduction

- bleeding risk reduction

- endothelial dysfunction improvement

- hypertrophy and remodelation of left

ventricle and resistence arterial

prevention

- plaque destabilisation risk reduction

- metabolic myocardial demand reduction

- nephropathy risk reduction

- retinopathy risk reduction

resist. art.

Adjustment of the hyperactivated regulatory mechanisms

hyperactivation of RAAS, SA,…XX- atherogenesis acceleration- trombogenic effect- hypertension developement- apoptosis activation- arrhythmogenic effect- vasoconstriction- fluid retention- ischaemia of live saving organs

-12

-8

-4

0

diuretics beta-block. ACE-I ARBs CCB

Comparison of the decline of BP with different antihypertensives monotherapy

(analysis of > 40 thousand hypertensives)

B

P r

ed

uc

tio

n in

mm

Hg

No significant difference of antihypertensives on BP reduction

Health Technology Assessment, 2003, 7, 31

Stroke incidence reduction in primary and secondary prevention

(analysis >200 st, >40 thousand hypertensives)

sfr

oke

inc

iden

ce

re

du

ctio

n (

%)

-35

-25

-15

-5

ACE-I ARBs CCB diuret. BB

25% 22%31% 26% 18%

Health Technology Assessment, 2007

ACE-I are the most effective in stroke prevention

-35

-25

-15

-5

ACE-I sartans CCB diuret. BB

21% 21%27% 23% 26%

Health Technology Assessment, 2007

CHD incidence reduction in primary and secondary prevention

(analysis >200 st, >40 thousand hypertensives)

CH

D in

cid

en

ce r

ed

uc

tio

n (

%)

ACE-I and BB are the most effective in CHD prevention

Appropriate and inappropriate combination of antihypertensives

diuretics -block.

sartansAT1R inhib.

ACE-I

CCBdihydropyridines

CCBnon-dihydrop.

Pulmonary hypertension therapy

Pulmonary artery resistance control

nitric oxide prostaglandins endothelins

cGMP rec. I2 a E2 rec. ETA , ETB

dilatation dilatation constriction

Pulmonary hypertension pharmacotherapy

• endotheline receptors antagonists

- nonselective A + B rec. – bosentan,

- selective rec. A – ambrisentan

• prostaglandine rec. agonists - PGI2, PGE2 and

analogs - iloprost (inhal.)

- epoprostenol (iv.)

• increase of cGMP availability - cGMP degradation inhibition by phosphodiesterase 5 blockers – sildenafil, tadalafil

Treatment of Hypotension

Hypotension treatment

• asymptomatic habitual hypotension - does not require treatment, only life mode modification

• symptomatic hypotension – after exclusion of secondary ethiology (drugs, bleeding,…), the circul. volume substitution, vasoconstrictive drug application is problematic

• hypotension in critical circulation deterioration

- specific therapy according to the mode of failure

Myocardial ischaemiatreatment / prevention

organic stenosis stable angina

vasospasmus vasospastic angina

thrombusunstable angina, MI

Myocardial ischemia ethiology

Coronary circulation curiosity

• left ventricle myocardial perfusion (in contrast to other organs) only in diastola

• maximal arteriovenose difference – no reserve for oxygen coronary circulation extraction

• minimal myocardial functional reserve – contractility failure even in mild ischemia

• enormous perfusion difference at rest and during the effort

Heart rate reduction importance• diastole prolongation → coronary perfusion

improvement + metabolic demand reduction

Vasodilatation in prevention of ischemia – perfusion improvement

( 70% of coronary stenoses are excentric)

Dynamic coronary obstruction in coronary organic stenosis – CCB and nitrate effect

intact coronary artery stenotic coronary artery

CCB+ CCB+

CCB-

CCB-

MYOCARDIAL ISCHEMIA – IMBALANCE OF DELIVERY AND COMSUMPTION

coronary organic stenosis,

spasm or thrombosis

↑ heart rate

↓ perfusion pressure (↓dTK)

↓ transport oxygen capacity

↑ heart rate

↑ contractility (catecholamines,…)

↑ left ventricle end-

diastolic tension

DELIVERY CONSUMPTION

O2

Myocardial ischaemiatreatment / prevention strategy

↑ coronary perfusion - revascularisation

- relaxation of the site of stenosis

- diastole prolongation

- optimal diastolic BP maintaining

myocardial demand - optimal heart rate

- optimal systolic BP (avoid ↑ BP)

- heavy physical burden reduction

metabolism optim. - preferential metabolism - glycolysis

(shifting from fatty acid β-oxidation)

Coronary perfusion improvement

- relaxation at the site of stenosis

• CCB (amlodipine, verapamil,…) • nitrates (molsidomine, ISMN, ISDN, GTN)

CAVE – steal phenomenon – rapid arteriolodilatation → ↓ BP → ↑ catecholamine → heart rate and oxygen consumption ↑

- diastole prolongation (heart rate ↓) • -blockers (opt. cardioselect., long-acting – bisoprolol,

…)

• non dihydropyridine CCB (verapamil)

• bradins (ivabradine)

Myocardial demand reduction

- heart rate slowdown

-blockers or non-dihydropyridine CCB (verapamil)

CAVE – substantial contractility reduction – leads to LV dilatation, BP drop-out, catecholamine wash out and metabolic demand increases

-blockers (opt. cardioselective and prolonged )CCB (verapamil)bradins (ivabradin)

- contractility reduction ???

CCB or nitrates ?

CCB

long acting (>24h)

- no tolerance developement

- positive prognostic effect

- more reliable effect

- antihypertensive effect

- arteriolodilatation (steal phenomenon induction)

NITRATES

- rapid onset of action

- effect concentrated to

epicardial part of

coronary bed (no steal ef.)

- short acting effect

- tolerance developement

- neutral prognostic effect

Ischemic myocardium metabolism optimalisation

• in mild ischemia, the glycolysis is used for ATP synthesis in the myocardium

• in severe ischemia (with pH drop-out due to lactate tissue accumulation), the glycolysis is inhibited and less effective fatty acid ß-oxidation is preferably used for ATP production

• conversion of FA ß-oxidation to glycolysis is possible to obtain ≈15% makroergic phosphate (ATP) in addition (trimetazidine effect)

0

25

50

75

100

125

150

175

200

225

Improvement of effort tolerance with drugs combination

no therapy CCB nitrates CCB + trimetazidine + -blocker (triple therapy)

%

+57%+44%

+41%+18%

Boden WE et al., 2007

Complex care - IHD patient

• thrombotic occlussion prevention

• plaque destabilisation and atherogenesis progression prevention • myocardial ischemia prophylaxis

• left ventricle remodelation and heart failure prevention

• arrhythmia occurence prevention

0

5

10

15

Effect of complex strategy in chronic CHD – serious vascular events and mortality

reduction

mo

rtal

ity

per

yea

r i

n %

life mode modification

+ aspirin or clopidogrel -25%

+ -block. -27%

+ statin -31%

+ ACE-I -23%

life mode modification

+ aspirin

life mode modification

+ aspirin+β-blocker

life mode modification

+ aspirin+β-blocker

+statin

Heart failure treatment

Pharmacotherapy od heart failure

contractility (cardiotonics, sympatomimetics):

quality of life improvement, no prognostic effect

fluid and electrolytes retention (diuretics): important quality of life improvement no data on prognostic effect

• sympaticus activation (-block., +-block.):

LV function, life quality and important

prognosis improvement

RAAS activity (ACE-I, aldosterone rec. inhib.):

LV function, life quality and prognosis improv.

Mechanism of beta-blockade in heart failure

1) antiischemic effect (myocardial perfussion improvement)

2) antiarrhythmic effect (fibrilation threshold increase, ventricle arrhythmia reduction)

3) hyperactivated regulatory mechanism inhib. - sympatoadrenal inhibition - renin-angiotensin-aldosterone syst. inhib.

4) apoptosis inhibition (cardiomyocyte number and contractility decrease prevention)

Mortality reduction in heart failure studies

-80

-70

-60

-50

-40

-30

-20

-10

0

carvedilol bisoprolol metoprolol

total mortality

pump failure

sudden death

US Carvedilol St. CIBIS II MERIT HF

65%

34%34%

Mechanism of ACE-I in heart failure

1)peripheral vascular resistence reduction (direct and due to bradykinine stimul.) - life important organs perfusion improvement and LV metabol. demand reduction

2) diuretic and natriuretic effect (direct and indirect - ADH + aldosterone release inhibition - fluid retention

3) noradrenaline release - sympathetic activity

4) fibrinolysis – thrombosis risk 5) apoptosis inhibition – contractility improvement

ACE-I effect on mortality reduction in heart failure(compared to placebo)

SAVEkaptopril

TRACEtrandolapril

AIREramipril

MORTALITY INCREASE MORTALITY DECREASE

N: 2 000

N: 2 000

N: 2 000

19%

22%

27%

100% 100%

ARBs effect in heart failure

• in comparison to ACE-I significantly less effective - on mortality/morbidity

• ARBs in heart failure indicated only in ACE-I intolerance (or in combination with ACE-I)

SAVE(kaptopril)

TRACE (trandolapril)

AIRE(ramipril)

19%

22%

27%

9%

100% 100%

CHARM (candesartan)

ACE-I

ARBs17%

VAL-HEFT (valsartan) 1%

CV mortality

ACE-I and ARBs effect on mortality in heart failure (compared to placebo)

MORTALITY INCREASE MORTALITY DECREASE

RALESspironolactoneserious chronic heart failure

EPHESUSeplerenone acute LV insuf.

REMINDEReplerenonepost MI with preserved LV function

EMPHASIS-HFeplerenonemild chronic heart failure

Aldosterone rec. inhibitors - in different heart failure types

RALESspironolactoneserious chronic heart failure

EPHESUSeplerenone acute LV insuf.

REMINDEReplerenonepost MI with preserved LV function

EMPHASIS-HFeplerenonemild chronic heart failure

Mortality (total and CV) reduction with aldosterone rec. inhibitors

↓ 27%

↓ 24%

↓ 15%

SAVE(kaptopril)

TRACE (trandolapril)

AIRE(ramipril)

19%

22%

27%

9%

100% 100%

CHARM(cardesartan) added

RALES(sprironolactone)27%

EPHESUS (eplerenone)15%

CIBIS II (bisoprolol)

MERIT HF (metoprolol)

34%

34%

US CARVEDILOL (carvedilol)65%

ACE-I

ARBs

aldost.antag.

-block.

17%

VAL-HEFT (valsartan) 1%

24%EMPHASIS HF (eplerenone)

Mortality reduction in heart failure (comparison with placebo)

MORTALITY INCREASE MORTALITY DECREASE

• beta-blockers – carvedilol (no bronchial obstruction, no hypotension) or bisoprolol, metoprolol, nebivolol

– titration to target dose in stabilised patient

• ACE-I – preferention of perindopril or ramipril – dose titration only in seniors or in hypotension

• aldosterone rec. inhib.– spironolactone (cheaper), eplerenone (better tolerated) in low (subdiuretic) dose

CAVE – real risk of hyperkalemia in combination of ACE-I with aldosterone rec. inhibitors (periodical K+ control)

Beta-blocker, ACE-I and aldosterone rec. inhibitors combination in heart failure

Mortality/morbidity reduction in chronic heart failure (analysis > 40 st., 36 000. pts.)

vasu

lar

even

ts r

edu

ctio

n

(%)

-35

-25

-15

-5

ACE-I ARBs ald.inh. CCB diuret. BB

3% 4%26% 23% 34%

Health Technology Assessment, 2007

Optimal combination: ACE-I + BB + aldosterone rec. inhib., no prognostic data for diuretic therapy

?21%

Diuretics in heart failure treatmentmanitol

acetazolamid manitol thiazidediuretics

loopdiuretics

potassium sparing

diuret.

metylxantiny

aquaretic

Diuretics in heart failure treatment• indication – fluid retention (pulmonary congest.,

oedema, ascites, hydrothorax) or hypertension

• fluid and electrolyte retention (diuretics) or pure water retention (aquaretics – tolvaptam)

• important quality of life improvement in heart failure, but no prognostic studiy available

• preference of most potent loop diuretic (furosemide or torasemide) or loop and thiazide diuretic combination

• in hypoosmolar fluid retention – aquaretics (rarely)

Positive inotropic drugs in heart failure treatment

a) contractility increase due to increase of calcium sarkoplasm concentration

• cardiotonics (digoxin) -sympatomimetics (dopamine, dobutamine,

denopamine) – only in acute failure

• PDE III inhibitors (amrinone, milrinone) - obsolent

b) contractility stimulation without sarkoplasmatic calcium concentration increase

• kalcium sensitisers (levosimendan,…) – in acute failure, increase affinity of Ca2+ to troponine C

CARDIOTONICS (cardioglykosides)

pharmacodynamic effect:

- myocardium – contractility improvement• autonomic nerve system – vagal activation

(negat. chrono- and dromotropic ef.)

• important interindividual plasma level variation – blood level monitoring initially

Increased mortality in elevated digoxine plasma level

(above the therapeutic range)

0

5

10

15

20

25

30

35

40

45

total mortality heart failure mortality

placebo

digoxine<0,9 ng/ml

digoxine≥0,9 ng/ml

mo

rtal

ity

(%

)

Heart failure therapy:

• ACE-I opt. perindopril or ramipril (all)

• -blocker carvedilol or selective -bl. (all)

• aldosterone rec. inhib. (spironolactone

or eplerenone - NYHA II-IV)

• ARBs (only in ACE-I intolerant)

• diuretics (in fluid retention)

• digoxin (in symptomatic pts or AFib )

• anticoagulants (in AFib, …)

0

20

40

Decrease of mortality in chronic heart failure – - combination therapyan

nu

al m

ort

alit

y i

n H

F p

ts -

%

digoxindiuretics

digoxindiureticsinhib. ACE

digoxindiureticsinhib. ACEspironolactone

digoxindiureticsinhib. ACEspironolactone-blocker

+ ACE-I -28%

+ spironolactone -27%

+ -blok. -34%

+ resyn- chron. -36%

study with ACE-I

study RALES

study-blok.

study CARE-HF

Thank you