Download pharm 24 [4-20

Chapter 24: Cardiac Contractility
Learning Objectives
1. What does phospholambin inhibit, bitch? How is it deactivated?

Phospholambin inhibits SERCA (SarcoEndoplasmic Reticulum Calcium ATPase), which pumps
calcium out of the myocyte and into the SR
 Phosphorylation by PKA de-activates phospholambin, up-regulating SERCA
2.
What directly stimulates PKA—what hormone will eventually activate it? What does PKA do?
 Adrenergic beta-1 agonists=> adenylyl cyclase=> cAMP=> PKA=>
 phosphorylates Calcium channels in the cell membrane and deactivates SERCA transporters
on the sarcoplasmic reticulum
 so β-adrenergic signalling is positively inotropic and chronotropic
3. Heart failure reduces the response to β-adrenergic signalling. How?
 HF causes increased production of Beta-adrenergic receptor kinase (beta arrestin), inhibitory
g-proteins, and inducible nitric oxide synthase
4. What drug blocks myocytes’ Na+/K+ ATPase, making it so that NCX can longer function due to
the accumulation of intracellular Na+? What are its 3 effects?
 Digoxin plugs the Na+/K+ ATPase, which means the myocyte can’t extrude as much Calcium
through the Na+/Ca++ exchanger (NCX)
 inotrope
 decreases AV node conduction velocity (like a Ca++ blocker) – which makes it good for
supraventricular tachycardia!
 Inhibits sympathetic outflow and increases parasympathetic tone
5. Why might digoxin blood levels vary among patients? What happens in digoxin toxicity? How do
you treat it?
 some patients have gut flora that metabolize digoxin (use antibiotics), chronic kidney disease
elevates levels, and hypokalemia increases digoxin’s effects
 Excess digoxin decreases AV node automaticity and increases His-Perkinje automaticity,
which can create a heart block and escape rhythm
 Treat digoxin toxicity with the irritant K+ intravenously, and use antidigoxin antibodies
6. What drugs does digoxin interact with (4)?
 Since β-adrenergic antagonists decrease AV nodal conduction, co-admin => heart block
[test Q]
i. However, this combo reduces HF mortality on the whole
 Verapamil, quinidine, and amiodarone increase digoxin levels because of reduced clearance
[the representative drugs of class IA, III, and IV]
7. How is digitoxin different from digoxin?
 Digitoxin is metabolized by the liver, so it can be used during renal failure
 Is not preferred because it has an extremely long half life
8.
Describe the effects of alpha-1 and -2, beta-1 and -2, and D adrenergic receptors:





α1 vasoconstricts peripheral vessles
α2 inhibits presynapse of NE nerves (feedback)
β1 is inotropic, lusotropic (diastolic relaxation), and chronotropic for the heart
β2 vasodilates the periphery
D1 vasodilates renal vessels—decreases afterload
9. How do low, intermediate, and high doses of dopamine differ? How is dopamine used?
 Low doses of DA stimulate D1 adrendergic receptors to vasodilate renal vessels
 Intermediate doses stimulate β1 and β2 receptors
 High doses stimulate alpha-1 receptors
[work your way up]
 DA is now only really used high dosage for its α1 stim (for sepsis/anaphylaxis), being
supplanted by dobutamine in cardiac cases
10. How does dobutamine improve upon DA?
 less likely to cause arrhythmias
 Dobutamine only stimulates β1 and β2 receptors
11. How does Epi’s effect change with dose? Use?
 Low dose: beta stim
 High dose: alpha stim causes vasoconstriction and increased afterload (acceptable)
 Used for cardiac arrest
[once again work upwards]
12. When do we use NE for heart conditions?
 Don’t. It’s fine for shock though
13. What is the synthetic β (mostly β1 and chronotropic) agonist?
 isoproterenol
14. What 3 PDE inhibitors are used in the heart? What are their effects and nickname? Drawbacks?
 Inamrinone & milrinone are PDE-3 inhibitors which work as “ino-dilators.” Theophylline is
older and is non-specific
 Inhibition of PDE3 means there is a higher cAMP concentration, inhibiting SERCA (see above),
improving contractility, diastolic relaxation, and rate of contraction
 good for short-term treatment of severely falling circulation
 10% of patients given inamrinone get thrombocytopenia; all cause increased mortality with
long term use