Physiological basis: contractility and pumping function
The basic and most important function of working cardiomyocytes is contractility, which is referred to in medical literature as inotropism. It is thanks to the coordinated contraction of these cells that the heart is able to perform its primary physiological task: to function as a continuous pump.
The pumping function of the heart is critically important for maintaining the viability of the entire organism. It ensures the uninterrupted delivery of the strictly necessary volume of blood to all peripheral tissues and organs.
The site of action of cardiotonic drugs is exclusively working cardiomyocytes. It is important to understand that their primary target is not vascular smooth muscle cells, endothelial cells, or elements of the cardiac conduction system, but precisely the contractile apparatus of the working myocardium.
Pathology: when cardiotonics are needed
When the pumping function of the heart decreases for any reason, a pathological condition known as heart failure (HF) develops. In this pathology, the heart loses the ability to pump a volume of blood sufficient to meet the needs of peripheral tissues.
Clinically, heart failure is classified into two main forms:
- Acute heart failure.
- Chronic heart failure.
It is specifically for the pharmacological correction of this condition and the stimulation of the weakened myocardium that cardiotonic agents are used. Their main therapeutic goal is to make the heart contract more strongly, overcoming the manifestations of failure.
Pharmacological effects and terminology
In pharmacology, the action of drugs that increase the force of myocardial contractions is strictly defined as a positive inotropic effect.
For a precise understanding of the subject, this effect must be distinguished from other types of effects on the heart. Cardiotonics primarily increase contractility specifically, which distinguishes them from drugs that predominantly affect myocardial excitability, heart rate (positive chronotropic effect), or impulse conduction velocity (positive dromotropic effect). Also, their action is directly opposite to the negative inotropic effect, in which contraction force decreases.
Classification by Mechanism of Action
All cardiotonic agents are divided into two major groups depending on how precisely they cause the cardiomyocyte to contract more strongly.
- Agents that increase the concentration of cytoplasmic calcium ($Ca^{2+}$).
For a muscle fiber to contract, calcium must accumulate inside the cell. The drugs in this subgroup increase the number of free $Ca^{2+}$ ions in the cytoplasm through various pathways. These include:
- Cardiac glycosides.
- $\beta_1$-adrenergic agonists (note: it is specifically $\beta_1$-receptors that are responsible for heart stimulation, unlike $\alpha_1$- or $\beta_2$-adrenergic agonists, whereas $\beta$-blockers, conversely, inhibit this function).
- Type III phosphodiesterase inhibitors.
- Agents that increase calcium sensitivity (calcium sensitizers).
Their uniqueness lies in the fact that they do not increase the absolute concentration of $Ca^{2+}$ ions inside the cell. Instead, they increase the affinity of the contractile protein troponin for the calcium already present. A prime example of such a mechanism is the drug levosimendan.
Classification by chemical structure
In addition to the mechanism of action, traditional pharmacology divides cardiotonics based on their chemical structure. This classification is extremely simple and includes two classes:
- Cardiac glycosides. These are drugs whose molecule has a characteristic glycoside structure.
- Non-glycoside cardiotonics. This is a broad, collective group that includes absolutely all other drugs with a positive inotropic effect that do not have a glycoside structure (including the adrenergic agonists, phosphodiesterase inhibitors, and calcium sensitizers mentioned above).
Briefly: answers to topical questions
What are the main medicinal products belonging to the group of cardiac glycosides?
The cardiac glycoside group includes drugs categorized by source into foxglove glycosides, Strophanthus gratus glycosides, and lily of the valley glycosides. Foxglove glycosides include Digoxin, Acetyldigoxin B, Lanatoside C, and Digitoxin. Strophanthus gratus glycosides include Ouabain (strophanthine G). Lily of the valley glycosides include Corglycon and Convallatoxin. In modern medical practice, Digoxin, Acetyldigoxin B, Lanatoside C, and Ouabain are used; Digitoxin and lily of the valley preparations are not included in the current list.
What drugs are included in the subgroup of type III phosphodiesterase inhibitors?
Milrinone belongs to the subgroup of type III phosphodiesterase inhibitors. It is used for the short-term treatment of acute heart failure resistant to other drugs. Ibopamine is mentioned among the orally administered agents developed to replace cardiac glycosides.
What specific agents belong to the group of beta1-adrenergic agonists with cardiotonic action?
The group of $\beta_1$-adrenoceptor agonists with cardiotonic action includes $\beta_1$-adrenergic agonists and dopaminomimetics. Specific drugs in this group are Dobutamine, which directly stimulates myocardial $\beta_1$-adrenoceptors, and Dopamine, which is a dopaminomimetic and a biochemical precursor of norepinephrine, exerting a cardiotonic effect through analogous receptor stimulation.
What is the precise biochemical mechanism of action of cardiac glycosides on cardiomyocytes?
The biochemical mechanism of action of cardiac glycosides consists in inhibiting the $K^+$-$Na^+$-ATPase enzyme in the cardiomyocyte membrane. This disrupts the efflux of sodium ions and increases its intracellular concentration, which alters the operation of the $Na^+$-$Ca^{2+}$ exchanger. As a result, the extrusion of calcium from the cell is slowed down, and its accumulation in the cytosol is increased with subsequent deposition in the sarcoplasmic reticulum, which ensures enhanced myocardial contraction.
What is the mechanism of action of type III phosphodiesterase inhibitors?
The mechanism of action of type III phosphodiesterase inhibitors consists in inhibiting phosphodiesterase III. Normally, this enzyme degrades cAMP to inactive 5'-AMP. Its inhibition leads to the accumulation of cAMP inside the cell, maintenance of protein kinase activity, opening of calcium channels, and increased influx of calcium ions into cardiomyocytes, which ensures enhanced contraction. In blood vessels, phosphodiesterase inhibition causes direct vasodilation, a decrease in total peripheral vascular resistance, and afterload reduction.
What main side effects are characteristic of cardiac glycosides?
Cardiac glycosides are characterized by cardiac and extracardiac side effects occurring during intoxication or overdose. Cardiac manifestations include rhythm and conduction disturbances, such as ventricular extrasystoles and atrioventricular block. Extracardiac effects encompass dyspeptic disorders in the form of nausea, vomiting, and diarrhea, visual disturbances with specific xanthopsia, as well as neurological and psychiatric disorders, including headaches, sleep disturbances, and hallucinations.
How does the chronotropic effect differ from the inotropic and dromotropic effects?
| Effect | Effect on cardiac activity |
|---|---|
| Inotropic | Change in myocardial contractility (enhancement of contractions in case of a positive effect) |
| Chronotropic | Change in heart rate (slowdown of rhythm in case of a negative effect) |
| Dromotropic | Change in the conduction velocity of excitation through the cardiac conduction system |
Thus, inotropism is responsible for contraction force, chronotropism for rhythm frequency, and dromotropism for conduction.
What absolute and relative contraindications exist for the prescription of cardiac glycosides?
The provided materials state that cardiac glycosides are contraindicated in atrioventricular block. Other absolute or relative contraindications to their prescription are not detailed in the study guides.
What are the pharmacokinetic features of levosimendan?
The pharmacokinetic features of levosimendan include a very high degree of plasma protein binding, which is 97–98%. The drug undergoes almost complete biotransformation in the body, yielding an active metabolite that accounts for 5%. The half-life of the parent substance is approximately 1 hour, ensuring a rapid onset of action.
To easily remember the two mechanisms of action of cardiotonics, imagine that calcium ions ($Ca^{2+}$) are loaders, and the protein troponin is the foreman. The first group of drugs (glycosides, $\beta_1$-adrenergic agonists, PDE III inhibitors) simply "hires more loaders," increasing the concentration of calcium in the cytoplasm. The second group (sensitizers, e.g., levosimendan) acts more cunningly: it does not increase the number of workers, but rather "gives the foreman a megaphone," increasing the sensitivity of troponin to the calcium already present.
Class and exam questions
What is inotropism and how is it related to cardiotonics?
Inotropism is the basic function of working cardiomyocytes, ensuring myocardial contractility. Cardiotonic agents possess a positive inotropic effect, meaning they purposefully stimulate and enhance this contractile activity.
Which specific cells do these drugs act upon?
The site of action of cardiotonic agents is directly on the working cardiomyocytes. They do not exert a primary stimulating effect on smooth muscle or endothelial cells, nor on the elements of the cardiac conduction system.
What is the fundamental difference between levosimendan and cardiac glycosides?
Cardiac glycosides enhance contraction by increasing cytoplasmic calcium concentration. Levosimendan, on the other hand, belongs to sensitizers: it does not change the concentration of $Ca^{2+}$ ions, but increases the affinity of the contractile protein troponin for them.
Which receptors do adrenergic agonists stimulate to achieve a cardiotonic effect?
The positive inotropic effect is achieved by stimulating $\beta_1$-adrenergic receptors. Drugs acting on $\alpha_1$- or $\beta_2$-receptors, as well as $\beta$-blockers, are not used for this purpose.
What else to study on this topic
- Detailed mechanism of action of cardiac glycosides at the cellular level.
- Pharmacodynamics of $\beta_1$-adrenergic agonists and type III phosphodiesterase inhibitors.
- Peculiarities of using cardiotonics in acute and chronic heart failure.
- Clinical significance of calcium sensitizers (using levosimendan as an example).
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