Inotropic agents-uses and limitations Flashcards
Name the general classes of positive inotropic agents
cardiac glycosides, B-adrenergic receptor agonists, phosphodiesterase inhibitors, Ca sensitizing agents
In general, what do positive inotropic agents do?
increase effective Ca conc
Examples of Cardiac glycosides
Digitalis (digoxin and digitoxin)
What are two accepted indications for use of digitalis?
1) treatment of chronic CHF in the presence of atrial fibrillation 2) treatment of chronic CHF when there is confirmed S3 gallop
Describe the use of digitalis in CHF with normal sinus rhythm.
Class II and II HF limited to systolic dysfunction show reduced probability of worsening HF, maintenance of exercise capacity and better quality of life.
Describe the results of the prospective, controlled trial with morbidity and mortality endpoints for digitalis
treatment with digitalis had no effect on overall mortality, modest reduction in deaths due to worsening of heart failure, higher incidence of sudden death (arrhythmias). Reduction in number of hospitalizations
Do patients with normal systolic function benefit from digitalis
No
Compare the chemical structure of digoxin from digitoxin
Digoxin has a hydroxyl at C12, where digitoxin does not
dosing of digitalis
effects are dose dependent and lower doses are much safer/more effective than higher doses
MOA of cardiac glycosides
Blocks Na/K pump, causing an increase in intracellular Na which leads to an increase in intracellular Ca b/c the Na/Ca exchanger is activated. Intracellular Ca is then reduced by the SERCA2 in the SR, the Na/Ca exchanger and a Ca pump in plasma membrane
Negative effects of digitalis
Increases intravascular Ca (can cause vasoconstriction), increases SNS, decreases NE reuptake
Positive effects of digitalis
increased PNS (vagal) tone, increased renal blood flow (thus decreasing blood volume) and positive inotropic effect decreases sympathetic tone by resolving symptoms of CHF
Relaxation of cardiac muscle is facilitated by?
Ca pump in SR, Na/Ca exchanger and active Ca pump
Effects of digitalis on myocardial conductions
Decreased conduction velocity in AV node and SA node with increased effective refractory period in AV node, enhanced excitability of Purkinje fibers, decreased refractory period and increased automaticity in ventricular muscle.
Explain how digitalis toxicity can produce premature ventricular contractions
Digitalis toxicity can lead to excess Ca in SR, thus the normal oscillatory release/uptake of Ca by SR is amplified by the overload. If the Ca oscillation is large enough to depolarize cell past threshold, it can lead to an inward current resulting in after-depolarization resulting in PVCs and other forms of ectopy.
EKG effects of digitalis
Increased PR interval, decreased QT interval, inverted T wave, ST segment depression
Pharmacokinetics of Digoxin and digitoxin
digoxin: 1.7day half life, renal excretion of unchanged drug (limited use if compromised renal function), limited hepatic metabolism. Digitoxin: 7 day half life, hepatic degradation with renal excretion of metabolites. Both are available orally
What is a digitalizing dose?
Steady state is not rapidly achieved for digitalis, so a loading dose is sometimes use
Digitalis toxicity
low therapeutic index, thus toxic side effects are common, especially if given with non-K sparing diuretics. Hypokalemia leads to increased intracellular Na and thus intracellular Ca. AV-block, premature ventricular contractions, bradyarrhythmias, ventricular fibrillations, anorexia, nausea, vomiting, etc
Treatment of digitalis toxicity
discontinue drug, slow infusion of K (if hypokalemia) will displace digitalis from bidning sites. If life threatening, digitalis specific antibody fragments
Digitalis drug interaction
ACEI increase K which prevents digitalis from binding. Diuretics can increase or decrease K. Ca blockers and beta blockers also slow AV nodal conduction. Erythromycin/tetracyclin decreases bioavailability. Amiodarone, quinidine decrease renal elimination
stimulation of B1 adrenergic receptors results in what? B2? A1?
B1= positive intotropy. B2= positive inotropy + vasodilator/ bronchodilator. A1= vasoconstriction
Name classes of positive inotropic agents other than cardiac glycosides
B adrenergic agonist (+/- alpha adrenergic activity) and phosphodiesterase inhibitors
Name Beta agonists and their functions
Norepinephrine has strong A1 and B1, with minimal B2 actions. Epinephrine has strong A1, B1 and B2 adrenergic actions. Dopamine has strong A1, slight B1 and minimal B2, with strong dopaminergic activity. Isoproterenol has NO A1, strong B1 and strong B2. Dobutamine has strong B1 and slight B2 activity.
What are dopaminergic actions relevant to HF
enhanced renal circulation producing diuresis
How is dopamine a direct and indirect agonist
it can cause release of synaptic NE as well as blocking its reuptake
compare low dose to high dose dopamine
low dose: vasodilatory. High dose: vasoconstrictor due to release of NE
Problems with positive inotropic agents
- Tachyphylaxis (desensitization, tolerance) 2. Substantially increased usage of myocardial oxygen
- Increased risk of sudden death (proarrhythmic)
- Generally not orally active
- Very short plasma half-life
Phosphodiesterase inhibitors MOA
Prevents breakdown of cAMP to AMP by phosphodiesterases and increases affinity of troponin-C for Ca, increases reuptake of Ca by SR and competitively inhibits adenosine receptors.
Evidence for use of PDEs
Type III PDEI in presence of beta blockers may be helpful and PDE V inhibitors may be useful in pressure overload HF. Overall, increase in mortality secondary to sudden death.
