Cardiotonic drugs

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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

Cardiac glycosides

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  purpureaStrophanthus  combeConvallaria  majalis  and other plants.

The chemical structure of CGs

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

Sympathomimetic drugs

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.

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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.

Indications:

1. Resistant HF,

2. Cardiogenic shock or acute myocardial infarction,

3. Traumatic, toxic, postoperative, hypovolemic shock.

β-Adrenomimetics

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

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.

Indications

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

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