Cardiac therapy: Inotropes and Inodilators Ettinger Flashcards
(24 cards)
Inotropes : Inodilators:
Inotropes are drugs that increase myocardial …………….
Inodilators also increase myocardial ……………, but have additional …………….. properties.
Inotropes are drugs that increase myocardial contractility. Inodilators also increase myocardial contractility, but have additional vasodilatory properties (Table 238-1).
Positive inotropes can produce dramatic hemodynamic effects, but also carry the potential for arrhythmogenesis. Calcium sensitizers are the newest generation of inodilators, and have performed well in recent canine clinical trials.
Positive inotropes can produce dramatic hemodynamic effects, but also carry the potential for arrhythmogenesis. Calcium sensitizers are the newest generation of inodilators, and have performed well in recent canine clinical trials.
POSITIVE INOTROPES
Digoxin-Cardiac glycoside
Digitoxin-Cardiac glycoside
Dobutamine-Catecholamine
Dopamine-Catecholamine
INODILATORS
Amrinone-PDE 3 inhibitor
Milrinone-PDE 3 inhibitor
Enoximone-PDE 3 inhibitor
Pimobendan- Calcium sensitizer/PDE inhibitor
Levosimendan-Calcium sensitizer
INOTROPIC MECHANISMS
Inotropes increase the force of myofiber……………independently of loading conditions.
This is achieved by altering the interaction between the contractile proteins and ………….., either by increasing ………… calcium concentrations, or by increasing ……………. to calcium.
Inotropes increase the force of myofiber shortening independently of loading conditions. This is achieved by altering the interaction between the contractile proteins and calcium, either by increasing cytosolic calcium concentrations, or by increasing sensitivity to calcium (Figure 238-1).
Digitalis compounds increase ……….. calcium by inhibiting the ……………….. pump, which leads to increased …………….. sodium concentrations. This promotes reverse-mode sodium-calcium exchange, and leads to increased calcium …………………
Digitalis compounds increase cytosolic calcium by inhibiting the sodium/potassium/ATPase pump, which leads to increased intracellular sodium concentrations. This promotes reverse-mode sodium-calcium exchange, and leads to increased calcium entry.
Catecholamines operate via the ………..-adrenergic signal transduction pathway, leading to increased …………. levels and increased ………… entry via ….-type ………….. channels.
Catecholamines operate via the beta-adrenergic signal transduction pathway, leading to increased cyclic AMP (cAMP) levels and increased calcium entry via L-type calcium channels.
PDE inhibitors antagonize the breakdown of …….. by PDE 3, leading to increased ………… entry in myocytes, and ………… via …………. light chain kinase in vascular …………..cells.
PDE inhibitors antagonize the breakdown of cAMP by PDE 3, leading to increased calcium entry in myocytes, and vasodilation via myosin light chain kinase in vascular smooth muscle cells.
Calcium sensitizers have a different mechanism of action, altering the sensitivity of the contractile proteins to …….. by their interaction with ……….-…. This results in a greater degree of shortening for the same intracellular calcium concentrations. Some calcium sensitizers also have some PDE inhibitory effects.
Calcium sensitizers have a different mechanism of action, altering the sensitivity of the contractile proteins to calcium by their interaction with troponin-C. This results in a greater degree of shortening for the same intracellular calcium concentrations. Some calcium sensitizers also have some PDE inhibitory effects.
INOTROPES
Digoxin
Digoxin is the most commonly used cardiac glycoside. Although it has been used in man for centuries, digoxin’s safety margin is small, and side effects are common.
Digoxin’s positive inotropic effects arise from ……………………….. inhibition and enhanced …………. entry.
The resulting inotropic effect is relatively weak compared to other inotropes, and digoxin’s additional central effects promoting …………… outflow may be more important to the clinical response.
In chronic heart failure, digoxin also results in resensitization of blunted …………………….. activity. Digoxin slows …………………. rate, and slows ………………….. conduction.
The decrease in heart rate reduces myocardial oxygen consumption, helping to offset any increase from its positive inotropic effects.
It also …………….. the effective r………………period, and can result in delayed afterdepolarizations.
Digoxin’s positive inotropic effects arise from sodium-potassium pump inhibition and enhanced calcium entry. The resulting inotropic effect is relatively weak compared to other inotropes, and digoxin’s additional central effects promoting vagal outflow may be more important to the clinical response. In chronic heart failure, digoxin also results in resensitization of blunted baroreceptor activity. Digoxin slows sinus node discharge rate, and slows atrioventricular (AV) node conduction. The decrease in heart rate reduces myocardial oxygen consumption, helping to offset any increase from its positive inotropic effects. It also prolongs the effective refractory period, and can result in delayed afterdepolarizations.
Digoxin: Its combination of increased intracellular ……….. concentrations and …….. effects can lead to a wide range of arrhythmias.
Its combination of increased intracellular calcium concentrations and vagal effects can lead to a wide range of arrhythmias.
Digoxin’s main indication in dogs is atrial fibrillation, because of its unique ability to slow ……………….response without causing a ……………. inotropic effect. Heart rate control is generally insufficient with digoxin alone, and other drugs such as diltiazem are often added to further slow AV node conduction
Digoxin’s main indication in dogs is atrial fibrillation, because of its unique ability to slow ventricular response without causing a negative inotropic effect. Heart rate control is generally insufficient with digoxin alone, and other drugs such as diltiazem are often added to further slow AV node conduction
Digoxin should be dosed according to lean body weight, and the dose should therefore be reduced in animals with marked fluid retention, or in ……………… animals (Table 238-2). The dose should also be reduced in ………………….
0.005-0.0075 mg/kg q12h or 0.22 mg/m2 PO
Digoxin should be dosed according to lean body weight, and the dose should therefore be reduced in animals with marked fluid retention, or in obese animals (Table 238-2). The dose should also be reduced in renal insufficiency
0.005-0.0075 mg/kg q12h or 0.22 mg/m2 PO
Drugs that decrease renal clearance of digoxin (such as furosemide) can increase the risk of toxicity, and hypokalemia can also increase plasma digoxin concentrations and exacerbate toxicity.
Drugs that decrease renal clearance of digoxin (such as furosemide) can increase the risk of toxicity, and hypokalemia can also increase plasma digoxin concentrations and exacerbate toxicity.
Digitoxin
Digitoxin is mainly metabolized by the liver, in contrast with digoxin. It is highly protein-bound, but shares with digoxin a highly variable half-life in dogs. It is rarely used in dogs nowadays, and never in cats.
Digitoxin
Digitoxin is mainly metabolized by the liver, in contrast with digoxin. It is highly protein-bound, but shares with digoxin a highly variable half-life in dogs. It is rarely used in dogs nowadays, and never in cats.
INOTROPES
Dopamine
Dopamine has a more prominent dose-dependent tendency toward ………..-…. effects than dobutamine, so can result in ………………….. Although at low doses it has similar effects to dobutamine, concern over possible ………………… effects makes it a less common choice in heart failure patients.
Dopamine
Dopamine has a more prominent dose-dependent tendency toward alpha-1 effects than dobutamine, so can result in vasoconstriction. Although at low doses it has similar effects to dobutamine, concern over possible vasoconstrictor effects makes it a less common choice in heart failure patients.
INOTROPES
Dobutamine: syntethic catecholamine with predom beta 1 adreneegic effects. It has a ultrashort half-life, so it is given inteavenously as a constant rate effusion. Potent positive inotrope with minimal effects on heart rate and systemic vascular resistancw at low doses, but some vasoconstrictor effects at higher doses.
Dobutamine:
Of value in cardiogenic chock. Its effects on cardiac beta -1 receptors are mediatee by a G protein mediatee activity on adenylcyclase and cAMP production.. Increased entry of calcium and ca-induced sarcoplasmic reticulum release of calcium results in increased contractility, increased rate of relaxation (positive lusitropy) and increased speed of conduction of impulses (positive dromotropy). At higher doses, tachycardia may develop as sinus node discharge rate increases, and the risk of tachyarrhytmias also worsens.
Due to downregulation of the adreneegic signaling pathway, with a reduction in the numbers of beta -1 receptors and uncoupling of beta 2, and cAMP is broken down by PDE3 during chronic sympathetic heart failure (and due to treatment witj dobutamine) the inotropoc reponse to dobutamine is significantly blunted in heart failure compared with normal dogs, although the chronoteopic effect persists.
INODILATORS
Milrinone
The bipyridine compounds milrinone and amrinone are PDE 3 inhibitors, and their effects are a result of the increased cAMP levels in both cardiac myocytes and vascular smooth muscle (increased contractility, improved lusitropy, venodilation and arteriodilation).
Milrinone inhibits PDE 3, leading to increased cAMP levels. This causes an increase in calcium release and reuptake in cardiac myocytes (positive inotropy and positive lusitropy) and relaxation in vascular smooth muscle cells (venodilation and arteriodilation). As with dobutamine, milrinone’s effect is markedly attenuated in both human and canine heart failure
The bipyridine compounds milrinone and amrinone are PDE 3 inhibitors, and their effects are a result of the increased cAMP levels in both cardiac myocytes and vascular smooth muscle (increased contractility, improved lusitropy, venodilation and arteriodilation).
Milrinone inhibits PDE 3, leading to increased cAMP levels. This causes an increase in calcium release and reuptake in cardiac myocytes (positive inotropy and positive lusitropy) and relaxation in vascular smooth muscle cells (venodilation and arteriodilation). As with dobutamine, milrinone’s effect is markedly attenuated in both human and canine heart failure
INODILATORS
Pimobendan
Pimobendan is a calcium sensitizer with PDE 3 inhibitory effect.
Mechanism of Action
Calcium sensitizers mediate their positive inotropic effects by increasing the …………… affinity of the regulatory binding sites of ………………, and thus achieve their effects without increasing ……………….. concentrations.
Many of the adverse effects seen with other positive inotropes (such as proarrhythmic risks) are believed to be associated with increases in …………. and abnormal …………….
INODILATORS
Pimobendan
Pimobendan is a calcium sensitizer with PDE 3 inhibitory effect.
Mechanism of Action
Calcium sensitizers mediate their positive inotropic effects by increasing the calcium affinity of the regulatory binding sites of troponin C, and thus achieve their effects without increasing cytosolic calcium concentrations. Many of the adverse effects seen with other positive inotropes (such as proarrhythmic risks) are believed to be associated with increases in cytosolic calcium and abnormal calcium cycling.
The exact ratio of calcium sensitizing effect to PDE 3 inhibition is difficult to determine in vivo. Pimobendan is metabolized in the ……….. to an active metabolite (UDCG-212) with more potent PDE 3 inhibitory effects than pimobendan itself, but the cardiac down-regulation of the ……………… pathway in chronic heart failure may …………. the impact of the PDE 3 inhibition (as seen with milrinone).
The exact ratio of calcium sensitizing effect to PDE 3 inhibition is difficult to determine in vivo. Pimobendan is metabolized in the liver to an active metabolite (UDCG-212) with more potent PDE 3 inhibitory effects than pimobendan itself, but the cardiac down-regulation of the cAMP pathway in chronic heart failure may reduce the impact of the PDE 3 inhibition (as seen with milrinone).
The PDE inhibitory effects of ………………….in the peripheral vasculature persist with heart failure, as this pathway is not down-regulated in the same way as in …………………
Pimobendan can also cause pulmonary arterial ………………….., which may be helpful in pulmonary hypertension.
The PDE inhibitory effects of vasodilation in the peripheral vasculature persist with heart failure, as this pathway is not down-regulated in the same way as in cardiac myocytes.
Pimobendan can also cause pulmonary arterial vasodilation, which may be helpful in pulmonary hypertension.
Pimobendan may have …………………. effects, and in experimental models has been shown to inhibit nuclear factor kappa B (NF-κB).
Pimobendan also has ………………. properties, which may prove useful in feline myocardial disease. Pimobendan (like levosimendan) has multiple pharmacologic effects, and its favorable effects on outcome in canine clinical trials may even be associated with its noninotropic effects.
In experimental models of canine heart disease, pimobendan produces an increase in contractility, ventricular relaxation, and reduction in pulmonary artery pressures.
Pimobendan may have anticytokine effects, and in experimental models has been shown to inhibit nuclear factor kappa B (NF-κB).
Pimobendan also has antithrombotic properties, which may prove useful in feline myocardial disease. Pimobendan (like levosimendan) has multiple pharmacologic effects, and its favorable effects on outcome in canine clinical trials may even be associated with its noninotropic effects.
In experimental models of canine heart disease, pimobendan produces an increase in contractility, ventricular relaxation, and reduction in pulmonary artery pressures.
The pharmacodynamic effects of pimobendan persist longer than expected considering the short half-lives of both pimobendan and UDCG-212, its main active metabolite. The oral bioavailability of pimobendan is significantly affected by food, so it should be administered at least an hour before a meal. It is usually started at the low end of the dose range (0.1 mg/kg q12h) but can be titrated upward to 0.3 mg/kg q12h.
The pharmacodynamic effects of pimobendan persist longer than expected considering the short half-lives of both pimobendan and UDCG-212, its main active metabolite. The oral bioavailability of pimobendan is significantly affected by food, so it should be administered at least an hour before a meal. It is usually started at the low end of the dose range (0.1 mg/kg q12h) but can be titrated upward to 0.3 mg/kg q12h.
INODILATORS
Levosimendan
Levosimendan is an inodilator licensed for use in human heart failure patients, and has recently challenged ……………….. as first choice for treating acute output failure. Levosimendan is a ………………… with inotropic effects, and a vasodilator as a result of …………….. channel activation.
In human patients it produces sustained hemodynamic improvement after intravenous infusion as a result of an active metabolite (OR-1896). Like pimobendan, it has additional ……………….. effects and may have antiapoptotic effects. Studies in human patients with acute decompensated heart failure have not consistently shown improved outcome with acute infusion of levosimendan versus dobutamine infusion, and an increased incidence of atrial fibrillation has been noted in at least one study.
Levosimendan is currently administered intravenously as a constant rate infusion, but an oral formulation has recently been developed. Studies of the oral formulation in healthy dogs and dogs with pacing-induced heart failure suggested that a daily dose rate of 0.025 to 0.05 mg/kg PO was sufficient to cause positive inotropic and lusitropic effects, and arteriodilation and venodilation without causing tachycardia.
Levosimendan
Levosimendan is an inodilator licensed for use in human heart failure patients, and has recently challenged dobutamine as first choice for treating acute output failure. Levosimendan is a calcium sensitizer with inotropic effects, and a vasodilator as a result of potassium channel activation. In human patients it produces sustained hemodynamic improvement after intravenous infusion as a result of an active metabolite (OR-1896). Like pimobendan, it has additional anticytokine effects and may have antiapoptotic effects. Studies in human patients with acute decompensated heart failure have not consistently shown improved outcome with acute infusion of levosimendan versus dobutamine infusion, and an increased incidence of atrial fibrillation has been noted in at least one study.
Levosimendan is currently administered intravenously as a constant rate infusion, but an oral formulation has recently been developed. Studies of the oral formulation in healthy dogs and dogs with pacing-induced heart failure suggested that a daily dose rate of 0.025 to 0.05 mg/kg PO was sufficient to cause positive inotropic and lusitropic effects, and arteriodilation and venodilation without causing tachycardia.
