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Flashcards in Adrenergic & Angiotensin Blockers Deck (24):

First major goal(s) of CHF tx

  • First and foremost, elimination of contributing factors must be attempted. This includes:
  • Reduction of hypertension
  • Reduction of Na+ intake
  • Weight reduction
  • Cessation of smoking


Mechanism of action of cardiac glycosides (and effects on contractility)

  • Cardiac glycosides ultimately act by increasing effective intracellular calcium.
  • Digitalis binds selectively and saturably to the α-subunit of the heterodimeric Na+/K+/ATPase, decreasing the rate of extrusion of intracellular sodium.
    • -->increase in intracellular sodium decreases the transsarcolemmal sodium gradient.
    • --> decrease in the rate of efflux of intracellular calcium + increase in the rate of influx of extracellular calcium via bidirectional NCX.
    • increase in intracellular calcium levels --> positive inotropic effect via enhancement of the interaction between actin and myosin.



Mechanism of action of β-adrenergic agonists (and effect on contractility)

  • β-adrenergic receptor is coupled to the G-protein Gs.
  • Stimulation of Gs increases adenylyl cyclase mediated production of cAMP from ATP.
  • ↑cAMP activates PKA; PKA phosphorylates phospholamban releasing inhibition of SERCA2
  • Active SERCA2 --> increasing calcium sequestration in the SR, and the LTCC, increasing its sensitivity to turn on calcium influx into the cell.
  • Overall, beta-adrenergic stimulation increases intracellular calcium and its cycling between the intracellular space and inside the SR —> an increase in inotropy and contractility is observed.


Mechanism of action of α-adrenergic stimulation (and effect on contractility)

  • α-adrenergic receptor is coupled to G-protein Gq.
  • Stimulation of Gq increase PLC mediated conversion of PIP2 into IP3 and DAG.
  • IP3 directly stimulates release of calcium from the SR.


Electrophysiological effects of cardiac glycosides @ AV node + clinical use

  • @ AV node, there is a decrease in conduction velocity and an increase in effective refractory period (ERP).
  • Modified by PNS and SNS (PNS control dominates)
  • The increase in the effective refractory period (ERP) of the AV node is the rationale for the use of cardiac glycosides in the treatment of supraventricular tachycardia, atrial flutter and atrial fibrillation.


Electrophysiological effects of cardiac glycosides @ conduction fibers/ventricular myocytes

  • excitability of the Purkinje fibers and specialized atrial conduction fibers is enhanced due to the increase rate of rise of phase-4 depolarization.
  • increase in automaticity can be proarrhythmic and at high doses, can cause PVCs, ventricular tachycardia and ventricular fibrillation.
  • cardiac glycosides are contraindicated in Wolff-Parkinson-White Syndrome—where there is aberrant AV conduction bypassing the AV node.
  • In ventricular muscle, effective refractory period is generally decreased and automaticity is increased—especially at toxic levels.


Main types of non-cardiac glycoside positive inotropic agents

  • Phosphodiesterase inhibitors (PDEs)
  • Beta-Adrenergic receptor antagonists


General MOA of PDE inhibitors

  • prevent the breakdown of cAMP by phosphodiesterase
  • increase the affinity of troponin C for calcium
  • increase the reuptake of calcium by the SR
  • can completely competitively inhibit the adenosine receptor


PDE-III bipyridine class = 



Advantages/Disadvantages of Milrinone

  • Milrinone appears to have few advantages over the beta-agonists other than lack of tachyphylaxis.
  • One advantage: for comparable degrees of inotropic stimulation, the PDE inhibitors appear to shift the MVO2 in a direction opposite that of beta-agonists.
    • appear to affect positively the balance between work and oxygen consumption.
  • Side effects: including excess mortality



Role of PDE-i (Milrinone) in CHF therapy

  • Not considered a first-line therapy in the treatment of mild, chronic CHF
  • may play a role in the treatment of moderate to severe CHF—especially when used in conjunction with certain beta-blocking agents


General MOA of Beta-Adrenergic receptor agonists

  • stimulation of the beta-adrenergic receptor by a beta-adrenergic agonist results in ↑cAMP production by adenylyl cyclase and subsequent PKA activation.
  • PKA-mediated phosphorylation of L-type Ca2+ Channels (LTCCs) and phospholamban (SERCA inhibitor) contribute to increased intracellular calcium levels and increased inotropy.


Major beta-adrenergic receptor agonists

  • epinephrine
  • norepinenphrine
  • dopamine
  • dobutamine


MOA/effects of epinephrine

  • high affinity for both alpha- and beta- adrenergic receptors.
  • @ Heart: 
    • positive inotropy is modulated by both beta1- and beta2- adrenergic receptors
    • positive chronotropy is modulated by just the beta2-adrenergic receptor.
  • IV administration; main indication is during the post-cardiopulmonary bypass setting when difficulty in removing the patient from the bypass pump is encountered


CHF effects on beta-adrenergic receptors

  • In patients with CHF, there is selective downregulation of the beta1-receptor, probably due to high levels of circulating catecholamines.
  • Thus, in the failing heart, beta2-adrenergic receptors become increasingly important—important to exploit this reservoir of potential for stimulating this pathway.


MOA/effects of norepinephrine

  • differs from epinephrine in that it is much less potent at beta2-receptors than at beta1-receptors.
  • Although it is a strong inotrope, it does not cause the peripheral vasodilation of low dose epinephrine and isoproterenol.
  • Also a potent alpha1-adrenergic receptor agonist—making it a potent vasoconstrictor and mitogen.


MOA/effects of dopamine

  • a direct and indirect agonist (as it also causes the release of synaptic norepinephrine and blocks its reuptake). Modest beta1- and alpha-adrenergic receptor activity.
  • Stimulation of dopaminergic receptors markedly enhances splanchnic and renal circulation→↑diuresis.
  • At lower doses, vasodilatory; at higher doses, via the release of norepinephrine, it can be a potent vasoconstrictor causing a significant increase in afterload.


MOA/effects of dobutamine

  • potent beta-agonist. Mostly beta1-selective.
  • IV dobutamine is used in the treatment of severe CHF to reverse decompensated condition.
  • Dobutamine appears to cause less beta-receptor down-regulation that other beta-agonists of similar efficacy, leading to a lower tendency for tachyphylaxis.


Vasodilators role in CHF therapy

  • Vasodilators decrease systemic vascular resistance (SVR), LV size, and MVO2.
  • Vasodilators may act preferentially at:
    • Arteries to reduce afterload—hydralazine, minoxidil and nifedipine (calcium channel blocker).
    • Veins to reduce preload—nitroglycerin and isosorbide dinitrate (ISDN)
    • Non-selectively at both arteries and veins—ACE inhibitors.



MOA of ACE inhibitors (+major drugs)

  • major drugs: captopril, enalapril, and lisinopril
  • inhibit ACE (angiotensin converting enzyme) and decrease production of AngII and destruction of bradykinin
  • create a net vasodilatory effect→↓BP.


Differences between various ACE inhibitors

  • Enalapril: slower onset and longer duration of action (1-2 times a day dosing). Prodrug Converted enalaprilat (can be given directly IV) in the liver.
  • Catopril: faster onset and shorter duration of action.
  • Lisinopril: even longer duration of action (once daily dosing).


Role of beta-blockers in CHF therapy

  • Patients with CHF have ↑ adrenergic drive as manifested by high levels of circulating catecholamines
  • Beta-blockers competitively block endogenous catecholamines from interacting with beta-adrenergic receptors --> reduce the metabolic demands associated with increased heart rate and myocardial contractility.
  • Prevents norepinephrine-induced beta-receptor down regulation and/or desensitization→ resensitizes the signal transduction pathway.
  • Use of beta-blockers over time = ↑CO, ↑EF and ↑submaximal exercise tolerance; ↓PA and LV end-diastolic pressures.



Disadvantages of beta-blockers

  • CHF patients have a limited cardiac reserve and must be titrated up to the correct dose of beta-blockers.
  • Patients may be uncomfortable and feel worse before they start feeling better (remodelling of the heart takes time—up to 3 – 12 months)
  • some patients may never reach the recommended dose
  • may not be tolerated in Class IV HF due to preexisting limitation in cardiac function


Major beta-blocker drugs

  • Metoprolol: beta1-AR selective agent
  • Carvedilol: relatively nonselective inhibitor of both beta1- and beta2- ARs and also alpha1-ARs (may explain vasodilatory action).