Cardiotonic agents, also known as cardiac inotropes or stimulants, have a positive impact on the myocardium (muscular layer of the heart) by enhancing its contractility. Unlike general inotropes, these agents exhibit a higher level of specificity as they selectively target the myocardium. They can be categorised into four distinct groups based on their unique mechanisms of action: cardiac glycosides, beta-adrenergic agonists, phosphodiesterase III inhibitors, and calcium sensitizers. It is important to note that certain medications, such as Milrinone and Digoxin, possess overlapping classifications due to their ability to engage multiple mechanisms of action. Their inotropic properties make cardiactonic agents critical in addressing inadequate perfusion, and acute heart failure conditions including cardiogenic shock, as well as for long-term management of heart failure. These conditions arise when the heart's ability to meet the body's needs is compromised.

Cardiac glycosides like digoxin, primarily inhibit the sodium-potassium pump (Na+/K+ ATPase), an important protein located on the surface of cardiomyocytes (cardiac muscle cells).^[1][2] Using ATP (the cell’s energy currency), this protein facilitates the transport of extracellular potassium ions (K+) into the cell while exporting sodium ions (Na+) out, maintaining a balanced 1:1 exchange.^[3] Thus, when this protein is blocked, Na+ accumulates within cardiomyocytes.

Moreover, cardiomyocytes possess another surface protein known as the sodium-calcium (Na+/Ca2+) exchanger. The accumulation of Na+ prompts its efflux from the cell, whilst concurrently allowing Ca2+ influx through this exchanger.^[4] Consequently, intracellular Ca2+ levels rise.

The interaction between Ca2+ and Troponin C (TnC) is significant, as it prepares muscle fibres for the sliding filament mechanism, which explains muscle contraction.^[5] With increased Ca2+ levels, interactions between Ca2+ and TnC intensify, leading to stronger contractions of the myocardiocytes.^[6] Therapeutic doses of cardiac glycosides have been shown to enhance cardiac contractility, benefiting patients with impaired cardiac function, such as those with heart failure.^[7]

Naturally produced hormones norepinephrine and epinephrine or synthetic drugs such as dobutamine can be collectively regarded as beta-agonists. Specifically, dobutamine selectively binds to β1 receptors located on the surface of specialised cardiac muscle cells.^[16] Relative to β2 receptors, β1 is the predominant type in terms of quantity and function within the heart.^[17]

Gs proteins are a subunit of a large family of receptors called G-protein-coupled receptors (GPCRs).^[18] Due to the coupling nature between β1, Gs proteins, and the enzyme adenylyl cyclase, activation of Gs proteins ultimately activates adenylyl cyclase, which is responsible for converting ATP into cAMP.^[19] Thus, beta-agonists will lead to elevated cAMP levels, which further activate a cAMP-dependent protein called protein-kinase A (PK-A).^[20] PK-A plays a pivotal role in increasing intracellular Ca2+ levels through 2 mechanisms:

• Phosphorylation of L-type Ca2+ channels results in their activation, leading to extracellular Ca2+ influx into cardiac myocytes.^[21]
• Phosphorylation at specific sites on the sarcoplasmic reticulum (SR), which is a compartment within cells that acts as the Ca2+ storage site.^[22] Phosphorylation results in the activation of ryanodine receptors (RyRs) on the surface of SR, resulting in Ca2+ release from this compartment into the cytosol (the universal fluid that bathes the different compartments inside cells)^[23]

Similar to the MoA of cardiac glycosides, elevated Ca2+ eventually translates into stronger cardiac contractile force.

PDE3 inhibitors exert their effects by blocking the activity of an enzyme called PDE3. This enzyme is responsible for breaking down a molecule called cAMP, which is the key signalling molecule in our body.^[31] When PDE3 is inhibited, the breakdown of cAMP is prevented, leading to increased levels of cAMP in our cells.^[32]

In our heart muscle cells, when the levels of cAMP rise, it activates a protein called protein kinase A (PKA).^[32] PKA acts as a switch, triggering a cascade of events that enhance the strength and efficiency of the heart's contractions.^[33] This ultimately leads to improved cardiac function.

PDE3 inhibitors also have an impact on the smooth muscles found in our blood vessels. By increasing cAMP levels, these medications cause the smooth muscles to relax.^[34] This relaxation has a significant benefit in our blood vessels as it leads to vasodilation, which means the blood vessels widen.^[34][35] Vasodilation helps to reduce resistance against blood flow, allowing for better circulation throughout the body.^[36]

Furthermore, PDE3 inhibitors exhibit an additional effect on platelets, which are small cell fragments involved in blood clotting.^[37] Increased levels of cAMP in platelets prevent their activation and reduce their ability to form blood clots.^[38] By inhibiting platelet aggregation, PDE3 inhibitors contribute to maintaining healthy and smooth blood flow.^[38]

Calcium is a vital element for regulating the contraction and relaxation of the heart muscle.^[6] Calcium sensitizers are medications that increase the responsiveness of heart muscle cells to calcium, enabling more forceful contractions while conserving energy.^[49] Contraction of the heart muscle relies on electrical signals that trigger the release of calcium ions. These calcium ions bind to a protein called troponin, which initiates the process of muscle contraction.^[50]

Calcium sensitizers function by binding to cardiac troponin C, thereby enhancing the sensitivity of heart muscle cells to naturally occurring calcium ions.^[51] This heightened sensitivity fosters a more efficient interaction between calcium and the contractile apparatus of the heart muscle.^[52] Consequently, calcium can more effectively bind to actin-myosin filaments, resulting in stronger contractions without excessive calcium accumulation.^[52] By reducing strain on the heart, this mechanism helps minimise the oxygen demand.

Furthermore, calcium sensitizers provide an additional benefit. They open potassium channels in the heart muscle cells, resulting in vasodilation and improved blood flow.^[53] This action reduces the workload on the heart.

Cardiotonic agents are typically employed as short-term and non-routine therapies for heart failure patients.^[71] They are specifically reserved for those with contractile dysfunction in the left ventricles (lower chambers of the heart), low cardiac output, and low blood pressure, placing them at risk of inadequate organ perfusion.^[72] While these agents assist in promoting perfusion, their potential for increased mortality and adverse side effects necessitates cautious administration at initially low doses, with careful adjustments under close monitoring.^[73][74] Given the diverse presentations of heart failure and individual patient characteristics, cardiotonic medication uses and preferences vary.

Specifically, in patients experiencing inadequate blood perfusion (with blood pressure below 80 mmHg), the American Heart Association / American College of Cardiology (ACC/AHA), recommends the use of Dobutamine and Milrinone.^[75] Whereas in clinically stable patients with sufficient perfusion, cardiac inotrope use is advised against.^[76] This caution is due to the heightened risk of adverse cardiovascular outcomes, including arrhythmias, detrimental heart structure remodelling, and even mortality.^[77][78] Heart failure can manifest in its life-threatening form of cardiogenic shock, with hypotension and low blood flow (hypoperfusion), placing the patient at risk of multiorgan failure.^[79] In cardiogenic shock management, cardiotonic agents serve 2 functions. Norepinephrine, epinephrine, dopamine, and phenylephrine contribute mainly through their vasopressor (vasoconstrictive) functions to constrict blood vessels to correct hypotension. Whereas, dobutamine, milrinone, enoximone, and levosimendan, act to restore the heart’s pumping function.^[80] To prevent further harm to the organs, cardiotonic agents are typically administered alongside oxygen, ventilatory support, and mechanical circulatory support (MCS).^[81] As hypoperfusion and organ dysfunction improve, it is recommended to gradually reduce the administration of these agents.^[81] However, certain patients who are unable to discontinue cardiotonic agents without experiencing recurrent heart failure symptoms, known as inotropic-dependent patients, may require prolonged usage.^[82] This serves as a bridge towards more invasive management approaches, such as transplants or left ventricular assist devices (medical device to assist the heart).^[83]

Heart failure patients are stratified based on their left ventricular ejection fraction, which quantifies the volume of blood expelled from the heart's lower chambers (ventricles) with each contraction.^[84] According to the European Society of Cardiology (ESC), among cardiotonic agents, Digoxin is specifically recommended as a second-line option for patients with an abnormal left ventricular ejection fraction (≤40%).^[85] Digoxin helps alleviate symptoms and reduce hospitalizations related to heart failure, but it does not offer any mortality-reducing benefits.^[86] Digoxin may be considered in patients who remain symptomatic despite receiving treatment with a first-line combination of an ACE inhibitor (or ARNI), a beta-blocker, and a mineralocorticoid receptor antagonist (MRA).^[87] It is also considered in patients with atrial fibrillation - a heart rhythm disorder characterised by irregular electrical impulses in the atria (the upper chambers of the heart).^[88] This abnormal electrical activity causes the atria to contract erratically, resulting in an irregular heartbeat.^[89] Treatment primarily focuses on restoring normal heart rhythm and controlling the heart rate to minimise the risk of complications, including stroke. According to the ACC/AHA guidelines, intravenous digoxin (cardiac glycoside) can be used in atrial fibrillation (Afib) to assist heartbeats.^[90] In multicenter randomised controlled trials, intravenous digoxin was shown to be effective in controlling the heart rate compared to a placebo.^[91][92]