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Mechanisms of action of positive inotropes: calcitropes (catecholamines, phosphodiesterase-3 inhibitors, digoxin), Levosimendan and Omecamtiv mecarbil
Inotropes are medicines that alter the force of contraction of the heart. By definition, there are positive inotropes that strengthen cardiac contraction, and negative inotropes that weaken it. However, when not specified otherwise, the term “inotrope” usually refers to positive inotropes, which are the topic of this video. Negative inotropes, such as beta blockers and calcium channel blockers, significantly overlap with antiarrhythmic agents, and are covered in another video.
Inotropes are used in conditions where there is a sudden low cardiac output, such as acute heart failure or cardiogenic shock. Cardiac output is the product of stroke volume – the amount of blood pumped in one heartbeat, and heart rate – the number of beats in one minute. More forceful contractions induced by inotropes pump more blood out of the heart, increasing stroke volume. Many inotropes also accelerate heart rate, which contributes to increased cardiac output.
Cardiac muscle contractions are triggered by a surge in intracellular calcium concentration. When cardiac muscle cells are stimulated by action potentials, calcium channels open, allowing calcium to rush in. This calcium influx activates ryanodine receptor on the membrane of the sarcoplasmic reticulum, the SR, causing more calcium release from the SR, in a process known as “calcium-induced calcium release”. Calcium then binds to troponin units on actin myofilaments and sets off muscle contraction by the sliding filament mechanism.
Most inotropes act by raising the levels of intracellular calcium; they can also be called calcitropes.
Many calcitropes operate via the catecholamine pathway. They bind to beta-adrenergic receptor, activating a signaling cascade that leads to production of cyclic-AMP, cAMP, a second messenger. cAMP promotes phosphorylation and hence activation of both L-type calcium channel that allows calcium influx from the extracellular fluid, and ryanodine receptor that mediates calcium release from the SR. The result is an increase in intracellular calcium that drives a stronger contraction. Most catecholamines have a short half-life and are given by continuous infusion.
Some other agents are inhibitors of the enzyme phosphodiesterase-3, PDE3. Because PDE3 breaks down cAMP, inhibition of PDE3 results in accumulation of cAMP and subsequent increase in intracellular calcium.
Digoxin, a widely used inotrope, acts by inhibiting the sodium-potassium pump, causing intracellular sodium concentration to rise. This then leads to higher levels of intracellular calcium via the action of sodium-calcium exchanger.
The problem with most calcitropes is that they increase contractility at the expense of cellular energy, meaning the heart muscle requires more oxygen to operate. This may lead to adverse effects including higher mortality. Other strategies have been explored to design inotropes that can boost cardiac output without increasing myocardial oxygen demand.
Levosimendan is a calcium sensitizing drug. It enhances troponin C sensitivity to intracellular calcium, thereby increasing the force of contraction without consuming more cellular energy.
Omecamtiv mecarbil, OM, is a new drug that is still under investigation. OM increases the efficiency of heart muscle contraction. It binds to cardiac myosin, stabilizing myosin-actin connection. This increases the number of myosin heads bound to actin, producing more force during cardiac contraction.
