Cardiovascular Toxicology

What is the formula for cardiac output?

heart rate x stroke volume

(CO = HR x SV)

What is the formula for blood pressure?

Blood pressure = cardiac output x systemic vascular resistance

(BP = CO x SVR)

Describe the flow of different ions during cardiac myocyte action potential

• Phase 0 (depolarization)

  • Ca and Na rush in

• Phase 1

  • Na channels close

• Phase 2

  • Ca comes in

  • K goes out

• Phase 3 (rapid repolarization)

  • K goes out

  • Ca channels close

• Phase 4 (resting potential)

  • Leaky K channels

When is the cardiac myocyte absolute refractory period?

Phase 0 - phase 3: a second action potential cannot be initiated

What are the roles of NKA and NCX pumps in reestablishing the resting state prior to the next AP?

• NKA pumps: reset intracellular K+ and extracellular Na+ levels

• NCX: use Na+ (moves in) gradient to extrude Ca2+ (moves out)

What is the P wave?

Atrial depolarization

What is the P-R interval?

Speed of conduction through AV node

What is the QRS complex?

Ventricular depolarization

What is the S-T segment?

Time which entire ventricular myocardium is depolarized

What is the T wave?

Ventricular repolarization

What is the Q-T interval?

Time for ventricular depolarization and repolarization

What are the effects of digoxin?

• ↑ contractility (inotropy) → ↑ stroke volume → ↑ cardiac output (CO = HR * SV) 

•  ↓ HR (chronotropy) to allow ventricles more time to fill → increase CO via increasing SV

• Increases CO and BP

What is the MOA of digoxin?

• Inhibits NKA pumps → increase intracellular Na and Ca, which causes more muscle contraction

• Increases vagal tone → decrease chronotropy

What are treatments for digoxin toxicosis?

• Activated charcoal

• Fluid therapy

• Antiarrhythmics

• Digoxin-specific antibody fragments (Fab)

What are beta blockers’ MOAs?

• B1 and B2 antagonism

• a1 antagonism for carvedilol

What are common effects of B blockers in an overdose?

• Bradycardia

• Hypotension

• Lethargy

• Weak, shaky

How do B blockers affect CO and BP?

Lower CO and BP

What are treatments for B blocker overdose?

• Emesis, activated charcoal, hemoperfusion

• IV fluids (for hypotension)

• Atropine (for bradycardia)

• Glucagon therapy

What is the MOA of CCBs (calcium channel blockers)?

• Affect L-type calcium channels in cardiac myocytes and vascular smooth muscle

  • Decrease chronotropy

  • Decrease inotropy

  • Decrease vascular resistance

What are common effects of CCB toxicosis?

• Hypotension

• Sinus bradycardia

• Sinus tachycardia

• Lethargy, depression

• Vomiting

What are treatments for CCB overdose?

• Emesis, AC, intralipids

• Fluids, calcium, vasopressors

• High-dose insulin/dextrose therapy (preferred therapy)

• Glucagon treatment (if others not effective)

What is the impact of NKA antagonism on intracellular and plasma K+?

• Intracellular: decrease

• Plasma: increase

Causes hyperkalemia

What is the impact of NKA agonism on intracellular and plasma K+?

• Intracellular: increase

• Plasma: decrease

Causes hypokalemia

How do CCBs affect blood glucose levels and intracellular glucose levels?

•  CCBs effects on glucose regulation: 

1) ↓ insulin release from pancreatic beta cells

• L-type calcium channels involved in insulin release

2) Inhibit protein kinase B in cardiac myocytes -> glucose transporter 4 (GLUT4) does not insert in plasma membranes

• Result: ↓ glucose in cardiac cells -> ↓ ATP production.

  • Increase glucose in blood

How do beta blockers affect blood glucose levels and intracellular glucose levels?

• Blood glucose levels: decrease

• Intracellular glucose levels: increase

• Decrease glucagon and increase insulin

How do beta agonists affect blood glucose levels and intracellular glucose levels?

• Blood glucose levels: increase

• Intracellular glucose levels: decrease

• Increase glucagon and decrease insulin

How does glucagon therapy function to treat beta blocker toxicoses?

• B1 adrenergic receptors and glucagon receptors mediate activation of cAMP → increase Ca2+ entry → improve inotropy

• Improves chronotropy by How does high-dose insulin/dextrose therapy function to treat CCB toxicoses?

How does high-dose insulin/dextrose therapy function to treat CCB toxicoses?

Insulin improves cardiac myocyte functioning:

1) ↑ inotropy (mechanism not entirely clear)

2) Provides more fuel for ATP production in myocytes.