Cardiotonic drugs are drugs, which increase cardiac contractile force during heart failure. Heart failure (HF) is a pathological state during which cardiac output is inadequate to provide the minute volume needed by the body or relatively normal minute volume and blood supply of the peripheral tissues is provided by the congested load of the heart.
Pathogenesis of HF
In 70 –75% of the cases disorder of the cardiac systolic function is observed, which depends on the cardiac muscle shortening degree during systole and CO. CO or minute volume of the heart depends on the following hemodynamic 3 factors.
1. End diastolic volume of the ventricles, so called preload, which depends on the circulating blood volume, cardiac blood return, efficiency of the atrial contraction etc. According to the Frank-Starling relation, cardiac contractile force directly proportional to the end-diastolic fiber length of the ventricles. End-diastolic fiber length of the ventricles depends on the preload.
2. Inotropic state of the cardiac muscle, which depends on the tone of the sympathetic nervous system, heart rate, mass of the functioning cardiac muscle, degree of the coronary blood flow.
3. Intracardiac tension, which should form ventricles during contraction to overcome resistance against which the heart must pump blood (so called afterload). Afterload depends on the pressure in aorta and pulmonary arteries, mass of the functioning cardiac muscles, sizes of the ventricular cavities.
During systolic HF pumping function of the ventricles is markedly decreased, during systole ventricles can`t develop sufficient wall tension to pump out an appropriate volume of the blood. In 25 –30% of cases a reason for development of HF is a diastolic dysfunction of the ventricles. In this case there is a deterioration of diastolic relaxation or diastolic feeling of the ventricles.
Thus, during HF, deterioration of 3 important hemodynamic factors can be noticed.
A. decrease in cardiac output
B. increase in afterload
C. increase in preload
According to the above mentioned pathogenetic mechanisms of HF, the main goals of the treatment of HF are:
1. Increase in cardiac contraction force (cardiotonic drugs)
2. Reduction of preload and afterload (vasodilators, diuretics, ACE–inhibitors)
3. Regulation of neuro-humoral system and prevention of heart remodeling (β-adrenoblockers, ACE -inhibitors)
Classification of cardiotonic drugs:
1. Cardiac glycosides/CGs/–Strophantine, Digoxin, Corglycon
2. Sympathomimetic drugs
2.1 β-adrenomimetics –Prenalterol, Xamoterol
2.2 Catecholamines and their derivatives –Dopamine, Dobutamine
3. Phosphodiesterase inhibitors
3.1 Bipyridine derivatives –Amrinone, Milrinone
3.2 Imidazole derivatives –Enoximone, Piroximone, Fenoximone
3.3 Benzimidazole derivatives –Pimobendane
4. Cardiotonic drugs with other mechanism -Vesnarinone, Forskolin
Demands for cardiotonic drugs are:
1. Reduction of tachycardia.
2. Absence of increase in oxygen demand of myocardium.
3. Reduction of central venous pressure
4. Absence of action on AV node
5. Efficiency during oral rout of administration and long duration of action
CGs are drugs of plant origin, don’t contain nitrogen, increase contraction force of the myocardium, without an increase of oxygen demand. In the medicine CGs were used in 500-1200 years as a vomiting drugs, in 1785 Uitering described and proved their usage. CGs are derived from Digitalis purpurea, Strophanthus combe, Convallaria majalis and other plants.
Classification of CGs
CGs are classified according to their level of polarity. There are 3groups:
1. Polar CGs (hydrophilic)-Strophanthine, Corglycone
2. With intermediate polarity-Digoxine, Celanide
3. Non polar CGs–Digitoxine, Gitoxine
Dopamine is an endogenous catecholamine.
Pharmacological and hemodynamic effects of Dopamine are dose-dependent. In low doses(2mcg/kg/min), Dopamine stimulates dopamine receptorsD1>D2(cAMP –dependent relaxation) and presynaptic D2 receptors (decrease of NE release and adrenergic stimulation), dilate the vessels. These receptors are prevalent in mesenterial and renal arteries.
In the same doses i/v injection of Dopamine improves renal blood flow and glomerular filtration rate. Also dopamine has direct effects on epithelial cells of renal tubules and through this mechanism also increases urination.
In the middle doses (2-5 mcg/kg/min), Dopamine directly stimulates β1-adrenoreceptors increasing cardiac output and stroke volume.
In higher doses (5-15 mcg/kg/min) Dopamine stimulates presynaptic β2-adrenoreceptors and increases NE release from presynaptic endings. Through this mechanism tachycardia is developed, sometimes even arrhythmias.
In very high doses(in 15 mcg/kg/min) Dopamine stimulates α 1-adrenoreceptorsand causes constriction of peripheral arteries and veins, also vessels of kidney. These doses are not used during HF because afterload of heart becomes increased, which worsens HF.
1. Resistant HF,
2. Cardiogenic shock or acute myocardial infarction,
3. Traumatic, toxic, postoperative, hypovolemic shock.
Prenalterol and Xamoterolare selective β1-adrenomimetics, increase heart stroke volume and oxygen demand, have also moderate diuretic effect. The above mentioned 2 drugs haven`t clinical practice, because by increasing heart oxygen demand, increase heart energetic processes, exhausting heart.
Dobutamine has a selective β1-adrenomimetic action. I/V injection of Dobutamine increases stroke volume of the heart. Also peripheral resistance and resistance of vessels of small blood circulation become decreased, renal and coronary blood flow is improved, excretion of sodium ions and water becomes stimulated.
Phosphodiesterase inhibitors (PDI)
These drugs are Amrinone, Milrinone, Enoximone, Piroximone, Fenoximone, Pimobendane etc. 7 types of phosphodiesterases (PD) are studied. These drugs block the third type of PD, which provides hydrolyses of cGMP-dependent cAMP. Due to these drugs, accumulation of cAMP is mentioned, which is activator of calcium channels in sarcolemma and sarcoplasmatic reticulum and increases calcium ions quantity in myofibrils.
Derivatives of bipyridins amrinone (INOKOR) and milrinone (KOROTROP) have no effects on heart rate, they increase force of contraction, dilate resistant and capacitive vessels and decrease pre-and afterload. Also they stimulate lipolysis, inhibit aggregation of thrombocytes and production of cytokins. Milrinone is 10 times more active than amrinone.
1. Chronic heart failure, when classical treatment is non effective.
2. Acute cardiac insufficiency Benzimidazole derivative -Pimobendane, besides inhibition of PDE, increases also acto-myosine sensitivity toward Ca2+ ions.
Cardiotonics with the different action mechanism
Vesnarinone induces opening of potential dependent Na and Ca channels, prolongs action of potential in heart muscle cells. It mainly inhibits PD III in heart and kidneys. It has positive inotropic effect, decreases heart rate and has antiarrhythmic and week vasodilating effects.
List of drugs
Strophanthin 0, 05%-1ml ampouls for injections
Digoxin /generic, Lanoxicaps, Lanoxin/ 0.125, 0.25 mg tablets; 0.05, 0.1, 0.2 mg capsules; 0.1, 0.25 mg/ml for injections
Dobutamine (generic, Dobutrex) 12.5 mg/ml 20ml flacons
Dopamine (generic, Intropin) 40 mg/ml 5 ml ampouls
Milrinone (generic, Primacor) 1 mg/ml for i/v injections; 200 mkg/ml, for i/v injections droply
Amrinone 20ml ampules, for i/v injections