Transcript Drugs used in the treatment of cardiac failure

DRUGS USED IN THE TREATMENT
OF CARDIAC FAILURE
(Summary)
Assoc. Prof. Iv. Lambev
www.medpharm-sofia.eu
Cardiac failure
develops as a
result of decreased
cardiac output,
when the heart
becomes unable to
provide adequate
amount of blood to
the organs according
to their needs.
Echocardiography
– ejection fraction
(EF) < 45%
I. CONGESTIVE HEART FAILURE (CHF)
The treatment of CHF aims to reduce preload
and afterload and to increase myocardial
contractility mainly by administration of:
ACE inhibitors, diuretics, beta-blockers,
alpha-blockers, cardiac glycosides,
organic nitrates, cardioprotecors, etc.
1. АСЕ inhibitors
Angiotensin
Renin
Angiotensin I
()
receptor
AT2-
receptor
Kinins
Angiotensin II
AT1-
ACE
inhibitors
ACE
(kininase II)
Breakdown
ACE
()
ACE inhibitors reduce pre- and afterload.
They are administered in lower doses alone
or together with diuretics, cardiac glycoside,
antiischemic agents, etc. in all stages of CHF,
due to systolic dysfunction.
In preparations with t1/2 ≥ 24 h (Perindopril,
Ramipril, Trandolapril) the risk of lowering
blood pressure after the first dose is avoided.
2. Thiazides and loop diuretics
They increase salt and water loss,
reduce blood volume
and lower excessive venous filling pressure,
reduce circulating blood volume and preload.
The congestive features of oedema, in the lungs
and periphery, are alleviated,
cardiac output is also increased.
Diuretics are administered together with
ACE inhibitors and other drugs.
Hydrochlorothiazide
Chlorthalidone
Indapamide
5%
20–30%
3. Cardiac glycosides (CGs)
France, UK
Nativelle
(1869)
•Digitoxin
Digitalis purpurea (Foxglove)
W. Withering (1785)
Digitalis
lanata
•Digoxin
The first
experiments
were carried
out by
Professor
P. Nikolov
(1894–1990),
(who was the
first head of
our Dept.)
Convallotoxin
Herba Adonidis vernalis
(Pheasant’s eye)
Convallaria majalis
(Lily of the valley)
(Aglycon)
(Glycon)
Ex
3Na+
Na+/K+
ATP-ase
(–)
2K+
3Na+
Na+/Ca2+
exchange
Ca2+
In
DIGOXIN
SR – Sarcoplasmic reticulum, TnC – Troponin C
Digoxin:
•Positive inotropic effect
without increasing of oxygen consumption
•Positive batmotropic effect
•Negative chronotropic effect
•Negative dromotropic effect
ARs: bradycardia, AV block,
Extrasystoles arrhythmias,
accumulation and intoxication.
Potassium and calcium have antagonistic action.
Hypokalemia and hypercalcemia potentiate
the action of CGs.
Specific antidote for digitalis
intoxication are Digoxin-specific
Fab-antibody (Digoxin Immune Fab – Digibind®,
DigFab®) in the form of intravenous infusion.
Antibodies interact also with
Digitoxin.
One vial of Digibind® (38 mg) or
DigFab® (40 mg) associated
approximately 0,5 mg
Digoxin or Digitoxin.
CGs are effective in CHF, occuring with
normal or accelerated heart rhythm,
especially in cases of atrial fibrillation.
Preparations of Digitalis (foxglove)
Digitoxin (t1/2 168 h)
Digoxin (t1/2 40 h): p.o. or i.v.
Semisynthetic derivatives of Digoxin
– Acetyldigoxin (Lanatilin®): p.o.
– Methyldigoxin (Lanitop®): p.o.
Preparations of Strophanthus gratus
– Strophanthin G (Ouabain®) – i.v.
4. Aldosterone antagonists
In cases of severe heart failure low
doses of Spironolactone are added to the
therapy while regularly checking creatinine
and electrolyte levels. Spironolactone
is a weak diuretic. It blocks aldosterone
receptors in the distal renal tubules
and reduces increased aldosterone
levels in CHF.
In low doses (25 mg/24 h) Spironolactone
potentiates the effects of ACE inhibitors.
It also saves K+ and Mg2+ and has antiarrhythmic activity. Spironolactone
prevents myocardial fibrosis, caused by
aldosterone, and in this way increases
myocardial contractility.
Similar to spironolactone is another
aldosterone antagonist – Eplerenone.
5. Beta- and alpha-blocking agents
Carvedilol is a blocker of β- and αreceptors. It also has antioxidant, vasodilating
and cardioprotective effects. It decreases
cardiac output, peripheral vascular resistance
and afterload. Carvedilol lowers mortality
with 25–67%, but it is contraindicated in CHF,
occuring with cor pulmonale. The treatment
begins with low doses (3.125 mg/12 h).
6. Beta-blocking agents
Cardioselective beta-blockers Bisoprolol and
Metoprolol decrease with 31% mortality in
patients with CHF, if used in combination with
diuretics, ACE inhibitors and Digoxin.
7. Оrganic nitrates
Organic nitrates dilate capacity vessels,
reduce preload and myocardium oxygen
needs. They connect with thiol groups (SH)
and release nitric oxide (NO).
NO combines with new thiol groups in
vascular endothelium to form nitrosothiol
(RSNO). Nitrosothiols activates guanylate
cyclase which raises the concentration of
cyclic GMP. This reduces the bioavailability
of intracellular calcium and produces
vasodilation.
Endothelium
Smooth muscle
Organic
nitrate
(RONO2)
Ca2+
Celullar action of nitrates
SR  sarcoplasmatic reticulum
GTP  guanosine triphosphate
GMP  guanosine monophosphate
In congestive left-ventricular
heart failure Isosorbide dinitrate
and Isosorbide-5-mononitrate are
prescribed.
To prevent tolerance
development are necessary
8–12 hours intervals without nitrates.
8.Prazosin
is a postsynaptic alpha-1-blocker which reduces afterload.
It is used for treatment of resistant CHF in low
doses together with diuretics and cardiac glycosides.
8. Metabolic cardioprotective agents
Trimetazidine has prolonged concentration
plateau lasting up to 11 h. It increases ATP
synthesis and decreases acidosis in ischemic
tissues. It supplies energy for Na+/K+
transmembrane pump,
but can cause parkinsonism.
Levocarnitine is a N-containing amino
acid in muscle, which has antioxidant activity.
It is indicated in cardiomyopathy and muscle
dystrophy caused by carnitine deficiency.
Preparations containing Coenzyme Q10
(a part of the mitochondrial redox system),
stimulate ATP synthesis and improve
myocardial contractility in CHF.
10. Calcium sensitizers
Levosimendan (Simdax®) increases
sensitivity of troponin in the heart
to calcium. This results in increased
myocardial contractility. It is infused
i.v. for short treatment of severe heart failure.
II. Acute heart failure (AHF)
1. Phosphodiesterase III inhibitors (PDE):
Amrinone, Enoximone, Milrinone
These agents are indicated in severe congestive
AHF, resistant to other drugs; usually for short
i.v. treatment. They have positive inotropic effect,
but they increase oxygen consumption.
ARs: ventricular and SV arrhythmias, angina,
hypotension, headache, hypokalemia.
Amrinone
Enoximone
Milrinone
(–)
ATP
AC
PDE III
cAMP
3’,5’-AMP
2. Cardioselective beta-1adrenomimetic agents
In AHF with cardiogenic shock Dobutamine
(β1-agonist) and Dopamine are administered
by i.v. infusion.
In high doses dopamine may increase
peripheral vascular resistance, while dobutamine
does not influence it.
Dopamine in low doses activates D2-receptors
in renal and mesenterial vessels and in coronaries. It causes arterial vasodilation, activates D5-receptors in myocardium and
increases myocardial contractility. Used in
low doses (2 to 5 mcg/kg/min i.v.) dopamine
does not increase blood pressure. In high
doses (> 5 mcg/kg/min i.v.) its α- and β-effects
dominate.
3. Organic nitrates
They dilate capacity vessels (vein, venules) which
normally can take up to 80% of the total blood volume.
They decrease intraventricular pressure and reduce
myocardial wall distention. Organic nitrates reduce
myocardial oxygen needs too.
Glyceryl trinitrate is prescribed sublingually at
18–20 min intervals in acute left-ventricular
heart failure, but it is more effective when
infused i.v. in doses from 10 to 100 mcg/min.
4. Non-organic nitrates
Sodium nitroprusside
is indicated in resistant to other
pharmacotherapy congestive heart
failure (often in combination with
dopamine) and also in acute
left-ventricular heart failure.
3. Alternative methods for treatment of severe CHF
Modern medicine often
disproves this saying.
“The heart never stops. When it stops, it stops
forever”. Leonardo da Vinci