Download heart rate

Summary of general
pharmacotherapeutic
approaches in cardiology
Jan Bultas, Debora Karetová
2013
Topics
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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 intervention
heart 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
Sinus rhythm - rate control
adrenergic
1 receptor
parasympathetic
muscarine rec.
calcium
T channel
calcium
L channel
natrio-potassium
channel If
potassium
channel Ik
Sinus rhythm - rate control
adrenergic
1 receptor
parasysympath.
muscarine rec.
-blockers
atropine
calcium
T channel
calcium
L channel
CCB /verapamil/
natrio-potassium
channel If
potassium
channel Ik
bradins –
If channel inhib.
Relation of heart rate and total
. and cardiovascular mortality
in males and females in the course of 20 yrs of follow-up
Benetos A et al. Hypertension 1999;33:44-52
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
mortality reduction (%)
timolol
metoprolol
propanolol
propanolol
practolol
oxprenolol
pindolol
heart rate slowdown (beats/min)
CV mortality and hospitalisation due to heart failure(%)
Relation of CV mortality to heart rate
(in quintiles of heart rate) – chronic HF
250 %
P<0,001
234%
200
P<0,001
180%
150
P=0,027
ns
100
133%
115%
100%
50
0
70 až <72
72 až <75
75 až <80
80 až <87
≥87
heart rate
SHIFT, Bohm M et al. Lancet 2010
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.
digoxin
I. cl.
Antiarrhythmics in atrial fibrillation
- sinus node rhythm restauration
propafenone
flecainide
sotalol
failure of other
antiarhythmics or
heart failure
amiodarone
contraindic.
in left ventricle
failure
Antiarrhythmics in atrial fibrillation
- reduction of ventricle rate by atrioventricular 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 (%)
Hypertension prevalence according to age
100
males
females
80,3
80
71,2
60,3 61,3
60
44,8 42,0
40
32,6
23,3
21,2
20
14,4
6,2
0
2029
9,9
3039
4049
5059
6069
70 age
Kearney et al. Lancet 2005;365:21723
CV mortality doubles
with BP increase by 20/10 mmHg
8x 
risk
8
4x 
risk
CV mortality
6
4
2
0
1x 
risk
115/75
2x 
risk
135/85
155/95
175/105
syst. BP/diast. BP (mmHg)
*Individuals aged 40–69 years
Lewington et al. Lancet 2002;360:1903–13
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
Comparison of the decline of BP with
different antihypertensives monotherapy
(analysis of > 40 thousand hypertensives)
diuretics
beta-block.
ACE-I
ARBs
CCB
 BP reduction in mm Hg
0
-4
-8
-12
Health Technology Assessment, 2003, 7, 31
No significant difference of antihypertensives on BP reduction
Stroke incidence reduction in
primary and secondary prevention
sfroke incidence reduction (%)
(analysis >200 st, >40 thousand hypertensives)
-5
ACE-I
ARBs
CCB
diuret.
BB
31%
25%
22%
26%
18%
-15
-25
-35
Health Technology Assessment, 2007
ACE-I are the most effective in stroke prevention
CHD incidence reduction in primary
and secondary prevention
CHD incidence reduction (%)
(analysis >200 st, >40 thousand hypertensives)
-5
ACE-I
sartans
CCB
diuret.
BB
27%
21%
21%
23%
26%
-15
-25
-35
Health Technology Assessment, 2007
ACE-I and BB are the most effective in CHD prevention
Appropriate and inappropriate
combination of antihypertensives
ACE-I
sartans
AT1R inhib.
-block.
diuretics
CCB
CCB
dihydropyridines
non-dihydrop.
Pulmonary hypertension therapy
Pulmonary artery resistance control
nitric oxide
prostaglandins
cGMP
dilatation
rec. I2 a E2
dilatation
endothelins
rec. ETA , ETB
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 ischaemia
treatment / prevention
Myocardial ischemia ethiology
organic stenosis
stable angina
vasospasmus
vasospastic angina
thrombus
unstable angina, MI
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
CCB+
stenotic coronary artery
CCB+
CCB-
CCB-
MYOCARDIAL ISCHEMIA – IMBALANCE OF
DELIVERY AND COMSUMPTION
DELIVERY
CONSUMPTION
O2
coronary organic stenosis,
spasm or thrombosis
↑ heart rate
↓ perfusion pressure (↓dTK)
↓ transport oxygen capacity
↑ heart rate
↑ contractility (catecholamines,…)
↑ left ventricle enddiastolic tension
Myocardial ischaemia
treatment / 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 (opt. cardioselective and prolonged )
CCB (verapamil)
bradins (ivabradin)
- contractility reduction ???
-blockers or non-dihydropyridine CCB (verapamil)
CAVE – substantial contractility reduction – leads to LV
dilatation, BP drop-out, catecholamine wash out and
metabolic demand increases
CCB or nitrates ?
NITRATES
CCB
- rapid onset of action
long acting (>24h)
- effect concentrated to
- no tolerance developement
- positive prognostic effect
- more reliable effect
- antihypertensive effect
- arteriolodilatation
phenomenon induction)
(steal
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)
Improvement of effort tolerance with drugs
combination
%
+18%
225
+41%
200
+57%
175
+44%
150
125
100
75
50
25
0
no therapy
Boden WE et al., 2007
CCB nitrates
CCB
+ -blocker
+ trimetazidine
(triple therapy)
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
Effect of complex strategy in chronic CHD –
serious vascular events and mortality
reduction
mortality per year in %
15
10
+ aspirin or clopidogrel
-25%
+ -block.
-27%
+ statin
-31%
5
0
life mode
modification
life mode
modification
+ aspirin
life mode
modification
+ aspirin
+β-blocker
+ ACE-I
-23%
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
US Carvedilol St.
CIBIS II
MERIT HF
0
-10
total
mortality
-20
34%
-30
34%
-40
65%
sudden
death
-50
-60
-70
pump
failure
-80
carvedilol
bisoprolol
metoprolol
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)
MORTALITY INCREASE
MORTALITY DECREASE
SAVE
kaptopril
19%
TRACE
trandolapril
22%
AIRE
ramipril
100%
27%
N: 2 000
N: 2 000
N: 2 000
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)
ACE-I and ARBs effect on mortality
in heart failure (compared to placebo)
MORTALITY INCREASE
MORTALITY DECREASE
19%
SAVE(kaptopril)
ACE-I
22%
TRACE (trandolapril)
AIRE(ramipril)
VAL-HEFT (valsartan)
CHARM (candesartan)
27%
1%
9%
ARBs
17%
CV mortality
100%
100%
Aldosterone rec. inhibitors
- in different heart failure types
RALES
EPHESUS
spironolactone
serious chronic heart
failure
eplerenone
acute LV insuf.
EMPHASIS-HF
REMINDER
eplerenone
mild chronic heart
failure
eplerenone
post MI with
preserved LV function
Mortality (total and CV) reduction with
aldosterone rec. inhibitors
RALES
spironolactone
↓ 27%
serious chronic heart
EPHESUS
↓ 15%
eplerenone
acute LV insuf.
failure
EMPHASIS-HF
eplerenone
↓ 24%
mild chronic
heart
failure
REMINDER
eplerenone
post MI with
preserved LV function
Mortality reduction in heart failure (comparison with placebo)
MORTALITY INCREASE
MORTALITY DECREASE
SAVE(kaptopril)
19%
TRACE (trandolapril)
22%
AIRE(ramipril)
VAL-HEFT (valsartan)
CHARM(cardesartan)
added
27%
1%
ARBs
9%
17%
27%
RALES(sprironolactone)
EPHESUS (eplerenone)
EMPHASIS HF (eplerenone)
CIBIS II (bisoprolol)
MERIT HF (metoprolol)
ACE-I
aldost.
antag.
15%
24%
34%
-block.
34%
65%
US CARVEDILOL (carvedilol)
100%
100%
Beta-blocker, ACE-I and aldosterone rec.
inhibitors combination in heart failure
• 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)
vasular events reduction (%)
Mortality/morbidity reduction in
chronic heart failure (analysis > 40 st., 36 000. pts.)
-5
ACE-I
ARBs
ald.inh.
26%
3%
21%
CCB
diuret.
4% 23%?
BB
34%
-15
-25
Health Technology Assessment, 2007
-35
Optimal combination: ACE-I + BB + aldosterone rec. inhib.,
no prognostic data for diuretic therapy
Diuretics in heart failure treatment
metylxantiny
manitol
acetazolami manitol
d
thiazide
diuretics
loop
diuretics
potassium
sparing
diuret.
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)
45
40
placebo
mortality (%)
35
30
25
digoxine
<0,9 ng/ml
20
15
10
5
digoxine
≥0,9 ng/ml
0
total mortality
heart failure mortality
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, …)
annual mortality in HF pts - %
Decrease of mortality in chronic heart failure –
- combination therapy
40
+ ACE-I
-28%
+ spironolactone
-27%
+ -blok.
-34%
20
+ resynchron.
-36%
0
digoxin
diuretics
digoxin
diuretics
inhib. ACE
study with
ACE-I
study
RALES
digoxin
diuretics
inhib. ACE
spironolactone
study
-blok.
digoxin
diuretics
inhib. ACE
spironolactone
-blocker
study
CARE-HF
Thank you