Cardiotonic drugs
Cardiotonic drugs
Cardiotonic agents are drugs which intensify the heart force. Normally, excitation of cardiomyocytes leads to the depolarization of the cell membrane. Entering the cytoplasm of a cardiomyocyte Са2+ ions perform the triggering function: increase of Са2+ ions release out of the sarcoplasmic reticulum. Са2+ ions stimulate ryanodine receptors of the membrane of sarcoplasmic reticulum. Ryanodine receptors are Са2+ - channels through which Са2+ ions leave sarcoplasmic reticulum for the cytoplasm. When ryanodine receptors are stimulated, the release of Са2+ ions out of SR increases; the level of Са2+ in the cytoplasm becomes higher. Са2+ ions bind troponin C (which is one of the components of troponin-tropomyosin complex); in this way they eliminate the inhibitory influence of troponin-tropomyosin on the interaction of actin and myosin. Actin-myosin interaction causes the contraction of a cardiomyocyte.
By the mechanism of action cardiotonics are grouped into:
( 1 ) Drugs increasing the amount of intracellular Са2+:
( a ) Na+, K+ - ATP inhibitors
Cardiac glycosides: Digoxine, Celanid, Strophanthine, Corglycon
( b ) Drugs increasing the amount of CAMP:
А. Due to the receptor activation of adenylatecyclase:
- Drugs dtimulating β1-adrenoreceptors:
- Dopamine, Dobutamine
B. Due to the inhibition of phosphodiesterase III
- Amrinone, Milrinone
( 2 ) Drugs increasing the sensitivity of myofibrils to Са2+
Levosimendane
Therefore, the following groups of drugs possess cardiotonic properties:
- Cardiac glycosides;
- β1 – adrenomimetics;
- Sensitizers of Са2+
- Cardiotonic agents of other groups.
Cardiac glycosides ( Pharmacodynamics of CG )
Cardiologic effects:
- Positive inotropic effect – increase of heart force without significant consumption of О2 by myocardium – direct, primary, cardiotonic effect;
- Negative chronotropic effect – inhibit sinus automatism. Bradycardia at the administration of CG is associated with the direct influence on pacemakers of SA-node and increase of n. vagus tone;
- Negative dromotropic effecr – inhibition of conduction through AV-node and His bundle.
Digoxin
Digoxin – a drug extracted from foxglove (Digitalis lanata), the main glycoside used in practical medicine. Absorption in intestine depends on the dosage form: in capsules – 70-76%; in solution – 54%; in tablets – 48%. It binds to blood proteins to 20-30%. Half-life period – 39 hours. 90% of digoxin is excreted with urine. In case of renal failure a daily dose should be reduced. The therapeutic effect is achieved in 1-2 hours; maximal effect – in 5-8 hours; general duration of action is 2-4 days. In emergency cases, i/v administration of digoxin in the solution with glucose is possible.
Digoxin is mainly used in case of chronic heart failure, especially for tachyarrhythmia.
Dosage forms: 0,25 mg tablets; for children – 0,1 mg. Prescribed for an oral use daily or every other day. Maximal daily dose for adults – 0,5 mg/day in 1-2 intakes. 1 ml 0,025% solution in ampoules is administered by bolus mixed with glucose solution or i/v drip in 200,0 ml of 5 % glucose.
Strophanthine K
Strophanthine К is extracted out of strophanthus plant. It is more active than the foxglove drug, it acts faster and for shorter time. It is prescribed if it’s necessary to rapidly restore the heart rate and force, sometimes for acute heart failure.
Pharmacokinetics. Water-soluble. It isn’t absorbed in intestine. It does not bind to blood proteins. The onset of action – 5-10 min, maximal effect after i/v administration is in 30-40 minutes. Half-life period – 12-24 hours. In the body Strophanthine does not undergo any transformations – it is excreted in an unchanged form (70-90%).
Strophanthine K is produced in 1 ml ampoules of 0,025% and 0,05% solution. It is administered i/v, with a bolus, slowly or by i/v drip mixed with 5% solution of glucose in the dose 0,25 – 0,5 mg.
Side effect of cardiac glycosides
( A ) Cardiac symptoms:
- ventricular extrasystoles;
- difficulty in AV-conduction;
( B ) Extra-cardiac symptoms:
- visual impairment (blurred vision, photophobia, yellow-green halo around visible objects);
- anorexia, nausea, vomiting (excitation of chemoreceptors of the trigger-zone in the vomiting center);
- diarrhea, stomachaches (activation of n.vagus, direct stimulating effect on GIT).
Toxic effect of cardiac glycosides
Toxic effect of cardiac glycosides is frequently observed as the margins of safety are too small. In case of an overdose there’s a risk of ventricular extrasystoles. The most serious form of arrhythmia that can be caused by cardiac glycosides – ventricular fibrillation. These drugs block AV-conduction. If overdosed, they can cause the disturbances of color vision, anxiety, disorientation, psychotic reactions (delirium, hallucinations). Toxic effects of CG are more prominent on the background of hypokalemia and hypomagnesemia and at the high level of calcium as well.
To eliminate the toxic effects of CG one uses potassium drugs (К+ ions prevent from glycosides binding to Na+/К+ - ATP) and magnesium drugs (Na+/К+ - ATP – Mg2+ - dependent enxyme). Potassium chloride solution is administered i/v. Potassium and magnesium aspartate, Panangin, Asparcam can be prescribed for oral or i/v use. I/v administration is required for disodium salt of ethylenediaminetetraacetic acid (Na2 EDTA; disodium edetate, трилон Б), that binds Са2+ ions in blood.
β2 – adrenomimetics
β2 – adrenomimetics – dobutamine and dopamine – are only used for acute heart failure for several days (no more). Longer use of β2 – adrenomimetics worsen the state of patients and increase the death rate.
Dobutamine (Dobutrex) – synthetic catecholomine.
Pharmacodynamics. It exerts cardiotonic action, increases myocardial contractions, increases stroke volume.
Indications:
- acute heart failure
- acute myocardial infarction
- cardiogenic shock
- chronic heart failure.
Pharmacokinetics. Parenteral administration. The onset of actions is in 1-2 min., duration – less than 5 min. Maximal effect at permanent infusion is achieved in 10 min. Т1/2 – 2 min. Elimination – 10 min. It is rapidly metabolized. Excreted by kidneys.
Dosage forms: 5 ml (50 mg/ml) ampoules and 250 ml bottles.
Side effects:
- nausea, vomiting;
- headache, tremor;
- tachycardia, extrasystoles;
- anxiety:
- Angina attack.
Contraindications:
- tachyarrhythmia;
- pheochromosytoma.
Phosphodiesterase III inhibitors
Non-catecholomine inotropic drugs – Milrinone, Amrinone, Enoximone.
Milrinone
Pharmacodynamics. Selective inhibition of phosphodiesterase III activity (the main type of enzymes in heart) and splitting of CAMP with an increase of Са2+. It increases cardiac output, dilate peripheral vessels, improve diastolic relaxation of myocardium, insignificantly increase the heart rate. Because of the arrhythmogenic effect it is rarely used.
Dosage forms: 0,1% - 10 ml ampoules. I/v administration. The control of the level of potassium in blood is required.
Troponin-tropomyosin complex in the muscle fibers of the heart has inhibitory effect on the interaction of actin and myosin and thus prevents the contraction of cardiomyocytes. Ca2 + ions bind troponin C (one of the elements of the troponin-tropomyosin) and eliminate the inhibitory effect of troponin-tropomyosin. Thus, the interaction of Ca2 + and troponin C helps to contract cardiomyocytes.
Levosimendan
Pharmacodynamics. Increases the sensitivity of troponin C to Ca2 + and increases the contraction of the heart. In high concentrations, it inhibits phosphodiesterase III, which inactivates cAMP. This contributes to cardiotonic action. Levosimendan has myotropic vasodilator action, which reduces the load on the heart in case of heart failure, dilates coronary blood vessels. Applied during acute left ventricular failure.
Pharmacokinetics. It has high bioavailability. T1/2 – about 1 hour. Metabolized in the liver. Excreted by kidneys.
Produced in vials of 0.25% - 10 ml (2.5 mg / ml). Administered in the form of bolus in solution of 5% glucose.
