Assoc. Prof. Iv. Lambev www.medpharm-sofia.euDRUGS USED IN THE TREATMENTOF CARDIAC FAILURE(Summary)

Cardiac failure develops as aresult of decreasedcardiac output,when the heart becomes unable toprovide adequate amount of blood tothe organs accordingto their needs.

106.psd

Echocardiography ejection fraction (EF) < 45%

The treatment of CHF aims to reduce preloadand afterload and to increase myocardialcontractility mainly by administration of:

ACE inhibitors, diuretics, beta-blockers,alpha-blockers, cardiac glycosides, organic nitrates, cardioprotecors, etc.I. CONGESTIVE HEART FAILURE (CHF)

1. inhibitors

Angiotensin

Angiotensin I

Angiotensin II

AT1-

receptor

AT2-

receptor

Renin

ACE

ACE

inhibitors

(-)

ACE

Kinins

Breakdown

(kininase II)

(-)

Angiotensin

AngiotensinI

Angiotensin II

AT

1

-

receptor

AT

2

-

receptor

Renin

ACE

ACE

inhibitors

()

ACE

Kinins

Breakdown

(kininaseII)

()

ACE inhibitors reduce pre- and afterload.They are administered in lower doses aloneor 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. SACUBITRIL & VALSARTAN film-coated tablets:

A combination of sacubitril (whose active metabolite sacubitrilat, blocks the enzyme neprilysin thatbreaks atrial and brain natriuretic peptide and reduced blood volume) and valsartan (inhitors of(angiotensin II1-receptors).Indicated for the oral treatment of adult patientswith CHF with reduced ejection fraction (FI).Brand names:Entresto and Neparvis in three fixedand graded doses

3. 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 lungsand periphery, are alleviated, cardiac output is also increased.

Diuretics are administered together with ACE inhibitors and other drugs.

2030%

Hydrochlorothiazide

Chlorthalidone

Indapamide

5%

4. Cardiac glycosides (CGs)

Digitalis purpurea (Foxglove)

W. Withering (1785)

France, UK

Nativelle

(1869)

Digitoxin

Digitalis lanataDigoxin

The first experimentswere carriedout byProfessorP. Nikolov(18941990),(who was thefirst head of our Dept.)

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Herba Adonidis vernalis(Pheasants eye)Convallaria majalis(Lily of the valley)Convallotoxin

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(Aglycon)(Glycon)

Na+/K+ATP-aseNa+/Ca2+exchangeCa2+3Na+

3Na+2K+DIGOXINExIn()

SR Sarcoplasmic reticulum, TnC Troponin C

Digoxin:Positive inotropic effect

without increasing of oxygen consumptionPositive batmotropic effectNegative chronotropic effectNegative 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 fordigitalisintoxicationareDigoxin-specificFab-antibody(Digoxin Immune Fab Digibind,DigFab)in the form ofintravenous infusion.Antibodiesinteractalso withDigitoxin.One vial ofDigibind (38mg) orDigFab (40 mg)associatedapproximately 0,5 mgDigoxin orDigitoxin.

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.CGs are effective in CHF, occuring withnormal or accelerated heart rhythm,especially in cases of atrial fibrillation.

In cases of severe heart failure low doses of Spironolactone are added to thetherapy while regularly checking creatinineand electrolyte levels. Spironolactone is a weak diuretic. It blocks aldosteronereceptors in the distal renal tubulesand reduces increased aldosteronelevels in CHF.5. Aldosterone antagonists

In low doses (25 mg/24 h) Spironolactonepotentiates the effects of ACE inhibitors.It also saves K+ and Mg2+ and has anti- arrhythmic activity. Spironolactone prevents myocardial fibrosis, caused byaldosterone, and in this way increasesmyocardial contractility.

Similar to spironolactone is anotheraldosterone antagonist Eplerenone.

Carvedilol is a blocker of - and -receptors. It also has antioxidant, vasodilatingand cardioprotective effects. It decreasescardiac output, peripheral vascular resistanceand afterload. Carvedilol lowers mortalitywith 2567%, but it is contraindicated in CHF,occuring with cor pulmonale. The treatmentbegins with low doses (3.125 mg/12 h).6. Beta- and alpha-blocking agents

7. Beta-blocking agentsCardioselective beta-blockers Bisoprolol andMetoprolol decrease with 31% mortality inpatients with CHF, if used in combination withdiuretics, ACE inhibitors and Digoxin.

10.psd

8. rganic nitrates Organic nitrates dilate capacity vessels,reduce preload and myocardium oxygenneeds. They connect with thiol groups (-SH)and release nitric oxide (NO). NO combines with new thiol groups invascular endothelium to form nitrosothiol(R-SNO). Nitrosothiols activates guanylatecyclase which raises the concentration ofcyclic GMP. This reduces the bioavailabilityof intracellular calcium and producesvasodilation.

Ca2+Organicnitrate(R-ONO2)EndotheliumSmooth muscleCelullar action of nitratesSR - sarcoplasmatic reticulum GTP - guanosine triphosphateGMP - guanosine monophosphate

In congestive left-ventricular heart failure Isosorbide dinitrateand Isosorbide-5-mononitrate areprescribed.

To prevent tolerance development are necessary812 hours intervals without nitrates.

9.Prazosin is a postsynaptic alpha-1-blocker which reduces afterload.It is used for treatment of resistant CHF in lowdoses together with diuretics and cardiac glycosides.

11.psd

10. Metabolic cardioprotective agents

Trimetazidine has prolonged concentrationplateau lasting up to 11 h. It increases ATPsynthesis and decreases acidosis in ischemictissues. It supplies energy for Na+/K+transmembrane pump, but can cause parkinsonism.(+ >>fish!)

121.psd

Levocarnitine is a N-containing aminoacid in muscle, which has antioxidant activity.It is indicated in cardiomyopathy and muscledystrophy caused by carnitine deficiency.

Preparations containing Coenzyme Q10 (a part of the mitochondrial redox system), stimulate ATP synthesis and improve myocardial contractility in CHF.

11. Calcium sensitizers

Levosimendan (Simdax) increasessensitivity of troponin in the heartto calcium. This results in increased myocardial contractility. It is infusedi.v. for short treatment of severe heart failure.

13.psd

II. Acute heart failure (AHF)1. Phosphodiesterase III inhibitors (PDE): Amrinone, Enoximone, Milrinone

These agents are indicated in severe congestiveAHF, resistant to other drugs; usually for shorti.v. treatment. They have positive inotropic effect,but they increase oxygen consumption. ARs: ventricular and SV arrhythmias, angina,hypotension, headache, hypokalemia.

ATP3,5-AMP ACPDE IIIAmrinoneEnoximoneMilrinone()cAMP

2. Cardioselective beta-1-adrenomimetic agents

In AHF with cardiogenic shock Dobutamine(1-agonist) and Dopamine are administered by i.v. infusion.In high doses dopamine may increaseperipheral vascular resistance, while dobutaminedoes not influence it.

Dopamine in low doses activates D2-receptorsin renal and mesenterial vessels and in coro-naries. It causes arterial vasodilation, acti-vates D5-receptors in myocardium and increases myocardial contractility. Used inlow doses (2 to 5 mcg/kg/min i.v.) dopaminedoes not increase blood pressure. In highdoses (> 5 mcg/kg/min i.v.) its - and -effectsdominate.

3. Organic nitrates

They dilate capacity vessels (vein, venules) whichnormally can take up to 80% of the total blood volume.They decrease intraventricular pressure and reducemyocardial wall distention. Organic nitrates reducemyocardial oxygen needs too. Glyceryl trinitrate is prescribed sublingually at1820 min intervals in acute left-ventricularheart failure, but it is more effective wheninfused i.v. in doses from 10 to 100 mcg/min.

4. Non-organic nitrates

Sodium nitroprusside is indicated in resistant to otherpharmacotherapy congestive heartfailure (often in combination with dopamine) and also in acute left-ventricular heart failure.

3. Alternative methods for treatment of severe CHFCardiac transplantaion

The heart never stops. When it stops, it stops forever. Leonardo da VinciModern medicine often disproves this saying.

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Angiotensin

AngiotensinI

Angiotensin II

AT

1

-

receptor

AT

2

-

receptor

Renin

ACE

ACE

inhibitors

()

ACE

Kinins

Breakdown

(kininaseII)

()

2030%

Hydrochlorothiazide

Chlorthalidone

Indapamide

5%

Digitalis

purpurea

(Foxglove)

W. Withering (1785)

France, UK

Nativelle

(1869)

Digitoxin