Inotropic Drugs Flashcards
Glycosides - Primary Mechanism
Glycosides block the Na+/K+ pump, decreasing the rate of extrusion of Na+
Increased intracellular Na+ augments the rate of Ca2+ influx through the NCX as it pumps to remove excess Na+
Increased Ca2+ leads to increased inotropy by virtue of more Ca2+ available to bind Tn-C
Effects of cardiac glycosides
Increased inotropy leads to: increased CO, increased EF, increased SV, decreased ESV and EDV
Decreased ESV and EDV result in decreased transmural wall pressure and reduced myocardial work
Increased CO also increases renal perfusion and GFR, resulting in diuresis and decreased blood volume
Alpha adrenergic agonists - Mechanism
Alpha adrenergic receptors activate Gq protein, which activates phospholipase C to produce DAG and IP3
IP3 activates Ca2+ release from the SR via IP3 receptors
Pro-arrhythmic effects of cardiac glycosides
Increased intracellular Ca2+ can lead to Ca2+ overload in the SR; if Ca2+ oscillation is large enough to depolarize the cell beyond threshold, it can lead to afterdepolarization and premature ventricular contraction or ventricular tachycardia or fibrillation
Beta-adrenergic agonists - Mechanism
Binding of agonist to the B-adrenergic receptor activates the Gs protein, which activates adenylylcyclase to produce cAMP; cAMP activates PKA which phosphorylates many protein targets including LTCCs and Phospholamban, increasing Ca2+ flux into the cell
Epinephrine / Adrenaline
Non-glycoside positive inotrope; sympathomimetic with B-adrenergic activity, binds both B1 and B2 adrenergic receptors
Phosphodiesterase Inhibitors
Prevent breakdown of cAMP by phosphodiesterase and increase the affinity of Tn-C for Ca2+
Persistent cAMP-PKA mediated phosphorylation of phospholamban increases the reuptake of Ca2+ into the SR
Norepinephrine
Non-glycoside positive inotrope; sympathomimetic with B-adrenergic activity, binds alpha1 receptors, B1 receptors, and B2 receptors with B1 activity > B2
Reduces vasodilation
Cardiac Glycosides - Secondary Mechanism
Glycosides increase CO, which increases renal blood flow; increased renal perfusion decreases circulating blood volume and diminishing activation of the RAS system
***Over time the positive inotropic effects of cardiac glycosides decrease sympathetic tone by resolving the symptoms of CHF
Digoxin - Pharmacokinetics
Polar compound with addition of an -OH group; compound administered IV and is excreted unchanged by the kidney with a half life of ~1.7 days
Digitalis- Side Effects
AV block
PVCs
Bradyarrythmias
Digitalis - DDIs
ACEIs - Increase K+ which displaces binding of Digoxin from Na+/K+ ATPase
Diuretics - can increase or decrease K+
Ca2+ channel blockers and B-blockers also slow AV nodal conduction
Digitoxin - Pharmacokinetics
Administered IV, excreted renally following hepatic degradation with a half life of ~7 days
Electrophysiologic effects of Digitalis on SA node
Decreased conduction velocity
Electrophysiologic effect of Digitalis on AV node
Decreased conduction velocity
Increased effective refractory period
