Cardiotonic agent

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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.

Contents

Classification

1) Cardiac Glycosides

Mechanism of action

Mechanism of action of cardiac glycosides (Digitalis): inhibition of Na+/K+ ATPase Mechanism of action of cardiac glycosides.png
Mechanism of action of cardiac glycosides (Digitalis): inhibition of Na+/K+ ATPase

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]

Pharmacotherapy profile

Drug examplesGeneral indicationsCommon side effectsCautionsSpecial populations
Digoxin [8]

Digitalis [8]

Digitoxin [8]

Heart failure with reduced ejection fraction [9]

Atrial Fibrillation (abnormal heart rhythm) [9]

Dizziness [10] [11]

Nausea [10] [11]

Diarrhoea [10] [11]

Skin rashes [10] [11]

Vision disorders [10] [11]

Arrhythmias [10] [11]

Vomiting [10] [11]

Impaired renal function [9]

Thyroid disorders [9]

Acute coronary syndrome (blood flow to heart muscle suddenly blocked) [9]

Electrolyte disorders (hypercalcemia, hypokalemia, hypomagnesemia) [12]

Pregnancy: can be used, may require dosage adjustment [13]

Breastfeeding: amount found in breast milk is insignificant, harm caused to foetus not well studied [14]

Renally impaired: consider reducing initial and maintenance doses [15]

2) Beta-adrenergic agonists

Mechanism of action

General mechanism of action of beta-adrenergic agonists: activation of b1 / b2 receptors Mechanism of action of beta-adrenergic agonists.png
General mechanism of action of beta-adrenergic agonists: activation of β1 / β2 receptors

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:

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

Pharmacotherapy profile

Drug examplesGeneral IndicationsCommon side effectsPrecautionsSpecial populations
Epinephrine [24]

Norepinephrine [24]

Dopamine [24]

Dobutamine [24]

Isoproterenol [24]

Anaphylactic shock [25] [26]

Cardiogenic shock [25] [26]

Cardiac arrest [25] [26]

Severe hypotension [25] [26]

Decompensated heart failure [25] [26]

Atrioventricular block (malfunction in heart's electrical system) [25] [26]

Arrhythmias (abnormal heart rhythm) [27] [16]

Chest pain [27] [16]

Hypertension [27] [16]

Palpitations [27] [16]

Anxiety [27] [16]

Acute myocardial infarction (heart attack) [16] [28]

Atherosclerosis (clogging of blood vessel wall) [16] [28]

Arrhythmias [16] [28]

Diabetes mellitus [16] [28]

Immediate use in cardiogenic shock or severe hypotension at risk of organ damage [29] [30]

3) Phosphodiesterase (III) inhibitors

Mechanism of action

Mechanism of action of PDE III inhibitors: inhibition of PDE3 enzyme Mechanism of action of phosphodiesterase enzyme (PDE) inhibitors.png
Mechanism of action of PDE III inhibitors: inhibition of PDE3 enzyme

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]

Pharmacotherapy profile

Drug examplesIndicationsCommon side effectsPrecautionsSpecial populations
Anagrelide [39] [40]

Cilostazol [39] [40]

Milrinone [39] [40]

Heart Failure [41]

Pulmonary Hypertension in babies [42]

Peripheral Vascular Disease [42]

Asthma [43]

Chronic Obstructive Pulmonary Disease (lung disease) [43]

Gastrointestinal discomfort [44]

Tachycardia (heart rate too fast) [44] Rapid drop in Weight [40]

Headaches [40]

Dizziness [40]

Insomnia [40]

Psychological disorder (for example anxiety) [45]

Compromised liver or kidney function with drugs that inhibit an enzyme called CYP3A4 [46]

Pre-existing ophthalmopathy (eye disorders) [47]

Avoid usage during pregnancy as it can inhibit meiosis, a specific form of cell division that takes place in oocytes, which are specialized reproductive cells in females [48]

4) Calcium sensitisers

Mechanism of action

Mechanism of action of calcium sensitizers: increase sensitivity of troponin C to Ca2+ Mechanism of action of calcium sensitizers.png
Mechanism of action of calcium sensitizers: increase sensitivity of troponin C to Ca2+

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.

Pharmacotherapy profile

Drug examplesIndicationsCommon side effectsPrecautionsSpecial populations
Levosimendan [54]

Milrinone [54]

Digoxin [54]

Heart failure (but no significant reduction in mortality) [55] [56]

Cardiogenic Shock [57]

Pulmonary Hypertension [58]

Post-Cardiac Surgery [59] [60]

Isolated tongue swelling [61]

Headache [61]

Nausea [61]

Palpitation [61]

Injection site irritation [62]

Renal and hepatic impairment [63] [64]

Electrolyte imbalance [65] [66]

Patients with prolong QT wave in ECG (abnormal repolarize time of heart) [67] [68]

Compelling indication in elderly patients with heart failure [69]

Positive effects in improving cardiac functions in paediatric (young) patients [70]

Clinical role in heart failure

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.

Cardiogenic shock leads to many harmful physiological effects Simplified scheme of cardiogenic shock.png
Cardiogenic shock leads to many harmful physiological effects

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]

Related Research Articles

<span class="mw-page-title-main">Cardiac glycoside</span> Class of organic compounds

Cardiac glycosides are a class of organic compounds that increase the output force of the heart and decrease its rate of contractions by inhibiting the cellular sodium-potassium ATPase pump. Their beneficial medical uses include treatments for congestive heart failure and cardiac arrhythmias; however, their relative toxicity prevents them from being widely used. Most commonly found as secondary metabolites in several plants such as foxglove plants and milkweed plants, these compounds nevertheless have a diverse range of biochemical effects regarding cardiac cell function and have also been suggested for use in cancer treatment.

<span class="mw-page-title-main">Sodium–potassium pump</span> Enzyme found in the membrane of all animal cells

The sodium–potassium pump is an enzyme found in the membrane of all animal cells. It performs several functions in cell physiology.

<span class="mw-page-title-main">Digoxin</span> Plant-derived medication

Digoxin, sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is one of the oldest medications used in the field of cardiology. It works by increasing myocardial contractility, increasing stroke volume and blood pressure, reducing heart rate, and somewhat extending the time frame of the contraction. Digoxin is taken by mouth or by injection into a vein. Digoxin has a half life of approximately 36 hours given at average doses in patients with normal renal function. It is excreted mostly unchanged in the urine.

<span class="mw-page-title-main">Digitoxin</span> Chemical compound

Digitoxin is a cardiac glycoside used for the treatment of heart failure and certain kinds of heart arrhythmia. It is a phytosteroid and is similar in structure and effects to digoxin, though the effects are longer-lasting. Unlike digoxin, which is eliminated from the body via the kidneys, it is eliminated via the liver, and so can be used in patients with poor or erratic kidney function. While several controlled trials have shown digoxin to be effective in a proportion of patients treated for heart failure, the evidence base for digitoxin is not as strong, although it is presumed to be similarly effective.

<span class="mw-page-title-main">Vasodilation</span> Widening of blood vessels

Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel walls are composed of endothelial tissue and a basal membrane lining the lumen of the vessel, concentric smooth muscle layers on top of endothelial tissue, and an adventitia over the smooth muscle layers. Relaxation of the smooth muscle layer allows the blood vessel to dilate, as it is held in a semi-constricted state by sympathetic nervous system activity. Vasodilation is the opposite of vasoconstriction, which is the narrowing of blood vessels.

<span class="mw-page-title-main">Troponin</span> Protein complex

Troponin, or the troponin complex, is a complex of three regulatory proteins that are integral to muscle contraction in skeletal muscle and cardiac muscle, but not smooth muscle. Measurements of cardiac-specific troponins I and T are extensively used as diagnostic and prognostic indicators in the management of myocarditis, myocardial infarction and acute coronary syndrome. Blood troponin levels may be used as a diagnostic marker for stroke or other myocardial injury that is ongoing, although the sensitivity of this measurement is low.

An inotrope or inotropic is a drug or any substance that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction.

cGMP-specific phosphodiesterase type 5 Mammalian protein found in Homo sapiens

Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum and the retina. It has also been recently discovered to play a vital role in the cardiovascular system.

<span class="mw-page-title-main">Phospholamban</span> Mammalian protein found in Homo sapiens

Phospholamban, also known as PLN or PLB, is a micropeptide protein that in humans is encoded by the PLN gene. Phospholamban is a 52-amino acid integral membrane protein that regulates the calcium (Ca2+) pump in cardiac muscle cells.

<span class="mw-page-title-main">Milrinone</span> Chemical compound

Milrinone, sold under the brand name Primacor, is a pulmonary vasodilator used in patients who have heart failure. It is a phosphodiesterase 3 inhibitor that works to increase the heart's contractility and decrease pulmonary vascular resistance. Milrinone also works to vasodilate which helps alleviate increased pressures (afterload) on the heart, thus improving its pumping action. While it has been used in people with heart failure for many years, studies suggest that milrinone may exhibit some negative side effects that have caused some debate about its use clinically.

<span class="mw-page-title-main">Amrinone</span> Chemical compound

Amrinone, also known as inamrinone, and sold as Inocor, is a pyridine phosphodiesterase 3 inhibitor. It is a drug that may improve the prognosis in patients with congestive heart failure. Amrinone has been shown to increase the contractions initiated in the heart by high-gain calcium induced calcium release (CICR). The positive inotropic effect of amrinone is mediated by the selective enhancement of high-gain CICR, which contributes to the contraction of myocytes by phosphorylation through cAMP dependent protein kinase A (PKA) and Ca2+ calmodulin kinase pathways.

k-Strophanthidin Chemical compound

k-Strophanthidin is a cardenolide found in species of the genus Strophanthus. It is the aglycone of k-strophanthin, an analogue of ouabain. k-strophanthin is found in the ripe seeds of Strophanthus kombé and in the lily Convallaria.

<span class="mw-page-title-main">S100A1</span> Protein-coding gene in the species Homo sapiens

Protein S100-A1, also known as S100 calcium-binding protein A1 is a protein which in humans is encoded by the S100A1 gene. S100A1 is highly expressed in cardiac and skeletal muscle, and localizes to Z-discs and sarcoplasmic reticulum. S100A1 has shown promise as an effective candidate for gene therapy to treat post-myocardially infarcted cardiac tissue.

<span class="mw-page-title-main">Troponin C type 1</span> Protein-coding gene in the species Homo sapiens

Troponin C, also known as TN-C or TnC, is a protein that resides in the troponin complex on actin thin filaments of striated muscle and is responsible for binding calcium to activate muscle contraction. Troponin C is encoded by the TNNC1 gene in humans for both cardiac and slow skeletal muscle.

A cardiac stimulant is a drug which acts as a stimulant of the heart – e.g., via positive chronotropic action and/or inotropic action. They increase cardiac output.

<span class="mw-page-title-main">Pimobendan</span> Chemical compound

Pimobendan, sold under the brand name Vetmedin among others, is a veterinary medication. It is a calcium sensitizer and a selective inhibitor of phosphodiesterase 3 (PDE3) with positive inotropic and vasodilator effects.

<span class="mw-page-title-main">Quazinone</span> Chemical compound

Quazinone (Dozonone) is a cardiotonic and vasodilator drug which was developed and marketed in the 1980s for the treatment of heart disease. It acts as a selective PDE3 inhibitor. It is no longer available.

<span class="mw-page-title-main">Omecamtiv mecarbil</span> Chemical compound

Omecamtiv mecarbil (INN), previously referred to as CK-1827452, is a cardiac-specific myosin activator. It is an experimental drug being studied for a potential role in the treatment of left ventricular systolic heart failure.

<span class="mw-page-title-main">Istaroxime</span> Chemical compound

Istaroxime is an investigational drug under development for treatment of acute decompensated heart failure

Cardiac excitation-contraction coupling (CardiacEC coupling) describes the series of events, from the production of an electrical impulse (action potential) to the contraction of muscles in the heart. This process is of vital importance as it allows for the heart to beat in a controlled manner, without the need for conscious input. EC coupling results in the sequential contraction of the heart muscles that allows blood to be pumped, first to the lungs (pulmonary circulation) and then around the rest of the body (systemic circulation) at a rate between 60 and 100 beats every minute, when the body is at rest. This rate can be altered, however, by nerves that work to either increase heart rate (sympathetic nerves) or decrease it (parasympathetic nerves), as the body's oxygen demands change. Ultimately, muscle contraction revolves around a charged atom (ion), calcium (Ca2+), which is responsible for converting the electrical energy of the action potential into mechanical energy (contraction) of the muscle. This is achieved in a region of the muscle cell, called the transverse tubule during a process known as calcium induced calcium release.

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