Alpha/Beta Agonists, Inotropes for BP and Cardiac Function

SV determinants

Preload, Afterload, and Contractility

Cardiac Output determinants

Afterload, preload, contractility, and Heart Rate

What is preload

Pressure that fills the ventricles. Increase in preload increases SV and CO.

Frank Starling Mechanism

The force of contraction of the heart increases in response to an increase in the volume of blood filling the heart (EDV), up to an optimal point. The more the heart fills with blood during diastole, the stronger the next heartbeat will be.

Afterload

The pressure/resistance the heart has to work against. Increase in afterload leads to a decreased SV and CO. Heart has to work harder to eject blood when afterload increases.

Contractility

The force generated by a given fiber length

High heart rate

Filling becomes impaired, preload decreases, SV drops

Smooth Muscle Contraction mechanism

1. Depolarization of smooth muscle causes calcium to be released from the SR

2. Calcium activates MLCK which phosphorylates the actin/myosin

3. Rho kinase inactivates MYPT to drive MLC phosphorylation

   1. Contraction occurs

Calcium induced calcium release

When a cell is already depolarized calcium enters the cardiomyocyte. It then activates ryanodine receptors on the SR which release more calcium. When contraction ends, intracellular calcium returns to the SR via SERCA.

Excitation Contraction Coupling

1. Action potential occurs, calcium flows into the cell

2. Calcium releases more calcium from SR through RyR2

3. Calcium binds to cTnC allowing actin/myosin to interact

4. Contraction Occurs

5. Calcium is removed by SERCA and is pumped back into the SR

6. Remaining calcium is removed by Na/Ca exchange

PLB

Inhibits SERCA

Alpha AR Receptors MOA in Blood Vessels

Increase Calcium influx into the cell. Increase PLC—→ PIP3 ——> increase Calcium —→ increase MLC phosphorylation and Rho-Kinase pathway

Uses of Alpha 1 Agonists

Shock

Causes of shock

Excessively low blood pressure and poor perfusion

Hypovolemic shock

Dehydration/hemorrhage

Distributive shock

Caused by inappropriate vasodilation from sepsis, anaphylaxis, etc.

Cardiogenic shock

Impaired function of the heart to maintain BP and CO

Obstructive shock

mechanical block of flow

Midodrine

Prodrug. Selective alpha 1 receptor agonist. Treatment for orthostatic hypotension, typically due to impaired ANS function.

Phenylephrine

Potent alpha 1 AR vasoconstrictor. May be used when tachyarrhythmias develop with NE, dopamine, Epi. Pt. has persistent shock despite use of 2 or more vasopressors/inotropes. Or pts. have high CO with hypotension.

Phenylephrine Effects

May decrease stroke volume and cardiac output in patients with cardiac dysfunction

When are Alpha 1 agonists used

Chronic orthostatic hypotension, acutely raise BP (emergency shock), non-systemic use (nasal spray, or local anesthetics)

NE

Major A1 and B1 activator. Increases MAP, SVR, and CO via B1 effects which increase contractility and HR. First line agent for septic shock. Strongly promotes vasoconstriction. I

Epinephrine

No alpha effects at low doses. Strong Beta 1 and Beta 2 effects. At high doses there will be an increase in SVR, pressure, HR, and contractility. Promotes vasoconstriction. Increases MAP and SVR in peripheral beds. Inotropic actions predominate at lower doses with vasoconstrictive actions happening at higher doses.

General CV effects of Alpha 1 AR Agonists

• increases in peripheral vascular resistance

• Decrease in venous capacitance, increase BP

• Will not directly impact HR/contractility

Alpha 1 AR agonists with some alpha 2 activity

Xylometazoline, Oxymetazoline. May be used in nasal decongestants and for nose bleed due to constriction of blood vessels and decrease blood flow to the epithelium. May cause hypotension in large doses if drug can cross BBB to the Alpha 2 receptors on the brain which will suppress sympathetic output.

Alpha 2 Agonists

Clonidine, Dexmedetomidine, apraclonidine, brimonidine. Use to treat hypertension through the CNS. Will likely produce bradycardia and sedation with clonidine.

Where do alpha agonists act

In the vasculature and sometimes the brain NOT the heart

When are beta agonists used

Severe hypotension, cardiac arrest, cardiogenic shock, low CO.

Are beta agonists supposed to be used long term

No. Increases hypertrophy, desensitization, increased O2 demand (ischemia), increased afterload due to effect on alpha AR

Beta 1 MOA in Nodal Cells

Activation of PKA and cAMP. PKA phosphorylates targets to increase the rate of firing. Increases sodium and voltage gated calcium channels. Increases action potentials/speed of conduction. Still contracts through Excitation-Contraction (E-C) Coupling.

Beta 1 MOA in Cardiomyocytes

Activation of PKA and cAMP is dependent on protein kinase. PKA phosphorylates ryanodine receptors, PLB, and SERCA. Increase calcium increase contraction.

Beta blockers

Slow the influx of sodium ions delaying the time it takes for the nodes to reach an action potential. Result in slower HR and decreased CO.

Acute HF

Injury usually treated with vasodilators, inotropes. Emergency treatment.

Chronic HR

Major cardiac remodeling like hypertrophy, fibrosis, or CAD. Treated with beta blockers, volume management, and vasodilators

Why use Vasodilators before inotropes

Vasodilators cause large decrease in afterload which should increase preload and provide sufficient perfusion to tissue

Adverse effects of beta agonissts

Ischemia, hypertension, arrythmia, tachycardia, bradycardia, tissue ischemia

Examples of Phosphodiesterase inhibitors

Milrnone, Amrinone

PDE inhibitors MOA

PDE degrades cAMP or cGMP. Inhibiting it increases calcium and promote contraction through increasing PKA signaling.

Digoxin MOA

Is a sodium potassium pump inhibitor. Inhibits the pump from increasing intracellular sodium levels. This increases the exchange of sodium and calcium through the sodium calcium exchanger. This increases intracellular calcium enhancing contractility. Mainly used in CHF patients.