Inotropic agents Flashcards
definition of contractility
-intrinsic property of cardiac muscle that determines the strength of contraction -independent of external loading, valve loading, valve function or filling pressure -cardiac performance is the entity which considers all of these parameters
All of the approved inotropes act by ________.
-increasing intracellular Ca (and cAMP) -the mechanisms by which additional Ca is released by SR varies with drugs and it is these mechanisms that determine potency and side effects
Famous example of cardiac glycoside
-digitalis aka digoxin
Digoxin, a cardiac glycoside inotrope, binds to what?
-binds to Na/K ATPase and blocks it; this causes Na to build up within the cell and turn on the Na/Ca exchanger. This exchanges Na with Ca, thus raising intracellular Ca which can increase contractility
Digoxin: effect on starling curve, inotropy, tolerance, mortality
-upward and left shift of starling -no desensitization/tolerance -increases inotropy WITHOUT increased HR - no increase in mortality at low doses
Digoxin structure
-lactone ring, steroid nucleus, sugar residues
Oral absorption, protein binding, half life, elimination, onset, max effect, duration, therapeutic level of digoxin
-60-75%; 25% protein bound -36 hr half life -RENAL elimination -5-30min onset via IV or 30-90 oral; max effect in 2-4 hrs IV and 3-6 oral -duration:2-6 days -Tx level 0.5-2 but really 0.5 to 1.0
Should you increase or decrease digoxin doses in pts with kidney disease?
-decreases!! it is renally excreted!
Digoxin hemodynamic effects
-increase CO -Increase LVEF -decrease LVEDP -increase exercise tolerance -inc natriuresis -decrease neurohormonal activation
Why are physicians not too worried about the increase in CO due to digoxin as further stressing an already failing heart?
-the increase in CO reduces the HR and PVR which offsets the increased myocardial demance for oxygen the increased contractility might create
Digoxin neurohormonal effects (5)
-decrease plasma NE: dec HR -decrease peripheral nervous system activity -decrease RAAS activity -increase VAGAL tone -normalizes arterial baroR
Digoxin EP properties
-affects atrial and ventricular muscle and pacemaker/conduction fibers differently due to direct effect of digoxin with neural effects -level of digoxin impacts which effects supercede
Digoxin effects on Atrial and AV node and ventricles
-atrial and AV: decreases automaticity via increase in vagal tone and decrease in sympathetic activity; increase refractory period of AV node (block/bradycardia issue in high doses) -ventricular tx doses increases inotropy while toxic doses can increase sympathetic tone and directly increase automaticity leading to risk of v. fib
Patients with CHF who had digoxin removed from their treatments did worse prognosis wise. Yet what was the overall mortality seen of digoxin in the DIG trial?
-no increase or decrease in mortality of pts vs placebo -survival similar to placebo, but have few hospitalizations for heart failure, more serious arrythmias (VT and V fib) and more MIs
Digoxin clinica uses
-A-fib with rapid ventricular response since it slows conduction in AV node; rate control; works better at rest than exercise -CHF symptoms despite medical therapy–NEED TO BE SYMPTOMATIC since it is beneficial in relieving symptoms -can be combined with other drugs
Goal levels of digoxin
-0.5- 1.0 to achieve benefit and avoid mortality
Factors predisposing to digoxin toxicity
-hypoK, hypoMg, hypothryoid, hypoxia -being on other drugs since drug interactions are VERY common!
Absolute and relative contraindications of digoxin
-absolute: digoxin toxicity -relative: advanced AV block without pacemaker, bradycardia or sick sinus without pacemaker, ventricular arrythmias or tachycardias, marked hypokalemia, Wolf-parkinson-white syndrome with a-fib since it will increase conduction through bypass tract which increases odds of ventricular arrhythmia
Digoxin toxicity locations
-cardiac: other card -GI: nausea, vomiting, diarrhea -CNS: depression, disorientation, paresthesias -Visual: blurred vision, scotomas, yellow-green vision -Hyperestrogenism: gynecomastia, galactorrhea
Digoxin cardiac toxicity
- arrhthmias: ventricular (PVCs, V Tach, V fib) or supraventricular: PAC, SVT 2. Blocks: SA and/or AV node blocks–MORE COMMONLY SEE THESE!! 3. Heart failure exacerbation: usually due to heart block/bradycardia
Treatment for digoxin toxicity
-specific antibody: Fab fragment directed against digoxin which rapidly reverses inhibiton of myocardial sodium pump -bound fragments excreted in urine -increase K to normal range to decrease digoxin binding to R but be careful not to overshoot
Stimulation of the SNS usually is mediated by what NT?
-NE
6 adrenergic agents and if used clinically
- dobutamine: yes 2. Dopamine: yes 3. Epinephrine: occassional 4. Isoproterenol: rarely 5. NE: occassional 6. Phenylephrine: yes(pressor!)
What allows dopamine to be especially handy?
-it has an incredible short half life so it is easy to make changes to its dosing
Affects of DA dosing
-at low doses: DA1R post synaptic leading to renal vasodilation and coronary and cerebral as well: renal dose dopamine -intermediate dose: DA2R (presynaptic) that inhibits NE reuptake (indirect B1 stimulation): inotrope!! -B1 and a receptors stimulated directly by high dose: pressor!!!
Dopamine side effects
-tachycardia (as dose increases) -HTN -nausea/vomiting -infiltration of IV site can lead to necrosis of skin or gangrene of fingers/toes due to vasoconstriction
Antidote for DA injection site skin necrosis
-Phentolamine
Dobutamine effects at low doses
-decreases afterload while increasing inotrophy -racemic mixture of isomers
Dobutamine dosing
-start at 2-3 ug/kg/min and titrate up to 20 max -continuous infusions causes desensitization -inhibited by B blockers so need higher doses here
Dobutamine half life
short acting; T1/2= 2 min -works quickly, usually without much hypotension
Dobutamine side effects
-arrythmias -ischemia/angina (can be used for stress test dx) -hypotension but less common than milrinone -tachycardia as dose increases -rapid ventricular response in a fib due to increase in AV conduction -nausea, headache, palpitations
Dobutamine as diagnostic agent
-take advantage of ischemic potential of it to dx coronary disease -pharm. stimulate exercise–useful in pts who cannot walk or ride a bike
T/F: Epinepherine is commonly used to treat CHF
false; used most commonly after cardiopulmonary bypass or in resuscitations -useful in denervated post-transplant heart
Half life and dosing of Epi
-very short half life -0.05 to 0.5 ug/kg/min
Side effects of epinepherine
-tachycardia -ischemia -platelet aggregation and infarction -anxiety, fear, restlessness
Function of NE
-powerful vasoconstrictor but only modest inotrope (sepsis and cardiogenic shock) -0.5-12 u/min
Does NE or Epi have more cardiac effects?
-Epi; NE basically is only a vasoconstrictor
Isoproterenol function and clinical use
-non-selective B-agonist with powerful chronotropic effect -used almost exclusively after heart transplant to drive HR and decrease PVR -dose; 0.005 to 0.05 u/kg/min
Phosphodiesterase type _____ is associated with the SR. Specific PDE inhibitors can increase ______ without an increase in _______.
-3 -contractility without increase in HR, esp at low doses
How can PDE III Inhibitors not increase HR?
-they act independently of B receptors
In addition to being inotropes and not chronotropes, what else are PDEI-3s?
- potent vasodilators including the venous capacitance vessels and pulmonary vascular bed -increase SV and decrease afterload!
- inotropic vasodilators
PDEIs in decompensated heart failure
- pharm effects should be beneficial in advanced HF
- improved systolic and diastolic function
- improved exercise tolerance
- excellent venodilator and pulmonary vasodilator
- inhibits platelet aggregation
- may inhibit proinflammatory cytokine formation
PDEI cautions
-can cause significant hypotension if filling pressures are not elevated due to the venodilator properties of PDEIs dropping preload
Currently available PDEIs
- amrinone
- milrinone
- both IV but oral PDEIs can be given now!
Why is amrinone rarely used?
- can cause significant thrombocytopenia especially in pts with advanced heart failure
- less potent than milrinone
Milrinone
- more potent selective PDE III Inhibitor
- long half life of 2.3 hours
- recommended to give bolus loading dose followed by maintenance infusion but rarely do this at Penn bc of hypotension risks
Milrinone elimination and implications
-80% eliminated by kidney (recall digoxin was too) so in renal failure patients, decrease in infusion rate by about 50%
Vesnarinone
- related to quinolinones
- oral med!!
- both PDEI inotrope and type III antiarrhthmic
- does not increase HR!!–advantage!
- increased risk of arrythmias including torsade de pointes–disadvantage
- improved quality of life but increased mortality
List 2 pros and cons of vesnarinone
- oral PDEI
- good: no increase in HR, improved QOL
- bad: increased risk of arrhthmia including torsade de pointes, increased mortality
Enoximone utility
- low dose is safe in advanced heart failure but does not produce sufficient efficacy
- therefore, not approved!
Pros and Cons of B-adrenergic therapy in HF
- pro: increased contractility
- con: weak vasodilator properties, worsens diastolic function, proarrythmic potential, tachycardia, desensitization
PDEI inotropic therapy pros and cons in decompensated HF
- pro: increased contractility, improved diastolic function, veno/vasodilator (systemic and pulm), no tachyphylaxis, effective in setting of B blocker therapy
- con: proarrhythmic potential, tachycardia, hypotenion, thrombocytopenia
Not only have oral inotropes been associated with excess mortality, but acute and chronic IV injections of both ____ and ______ have been associated with excess mortality.
- dobutamine
- milrinone
IV inotropic therapy patient selection
- acute: decompensated with V overload and impaired perfusion, V overload with diuretic resistance and/or organ hypoperfusion–including low CO states
- chronic: transplant listed recipients as a bridge; refractory HF sxs after maximal medical therapy as palliation
3 classes of inotropic agents
- cardiac glycosides
- B-agonists
- PDEIs
