E4L3

Ventricle contraction delayed 0.12 to 0.20 seconds.

-perfectly timed to account for the physical passage of the blood from the atrium to the ventricle

Membrane potential controlled by several ions

  -Na+, Ca2+, K+ and Cl-

Dependent on:

  1. Extracellular vs. intracellular concentrations   2. Membrane permeability

Voltage-gated or Ion-gated channels

  -prevent free diffusion

  -create electrical and chemical concentration   gradients

Phase 4- gradual depolarization

  -reset of automaticity

Phase 0- spontaneous rapid

  depolarization

  -Na+ ions rush in

Phase 1- initial re-polarization

  Ca2+ influx

  -L channels

  -triggers heart pump

Phase 2- calcium influx wanes

  -K+ re-polarization

Phase 3- Potassium efflux

-Reduced AP duration, slowed conduction, decreased pacemaker rate

  -Prolonged AP duration,

  increased pacemaker rate

  -increased arrhythmias,

  Torsade de points

Electrical gradient in Purkinje fiber

  -Normally -70 to -90 mV (distribution of Na+, K+ and Ca2+)

P wave: atria contraction/   depolarization

QRS complex: ventricular

depolarization

RST segment = contraction

T wave: re-polarization of ventricles

• P wave, atria depolarize
  
• PR interval (wave and segment)- current moves from SA   node to AV node
  
• Q R S waves- signal travels through ventricles
  
• ST segment (region between waves) = contraction
  
• T wave = re-polarization of ventricle.
  

Bradyarrhythmias: abnormally low heart rates.

Often due to structural defect of the heart.

Therapy involves implantation of a mechanical pacemaker.

Tachyarrhythmias: abnormally high heart rates.

More common clinical problems.

Causes are diverse: drugs, ischemia, cardiomyopathy, etc.

Treated with anti-arrhythmic drugs.

Disturbances in impulse formation

enhanced automaticity

Lower TP = increased contraction rate

Shortened diastolic interval

Caused by increased Phase 4 slope or lower TP

  -Induced by: Hypokalemia, beta agonists,

  fiber stretch, partial depolarization by injury   current.

EAD exacerbated by slow heart rates (long QT

Example: Torsade de pointes

Caused by:

AV node or bundle branch block

Unilateral Blocks (Re-entry)

To occur:

  1. Obstacle to conduction

  2. Unidirectional block

  3. Conduction around circuit outlasts refractory period

One impulse excites areas of the heart more than once

  -localized to AV node

  -Large area in atrial or ventricle walls

  Multiple re-entry circuits meander through heart (Afib/Vfib)

Unilateral Blocks (Re-entry)

Local site of reentry within atrium

  -causes atrial tachyarrhythmia

Signal repeatedly stimulates atrial branches

Atrial flutter

Unilateral Blocks (Re-entry)

Ventricular fibrillation is typified by chaotic irregular appearance without discrete QRS waves.

Local site of reentry within ventricle

  -causes ventricle tachyarrhythmia

Signal repeatedly stimulates ventricle branches

1. Sodium channel blockade

2. Block sympathetic autonomic effects in the heart

  (beta-adrenoreceptor drugs)

3. Prolong the refractory period (target K+ channels)

4. Calcium channel blockade

1A (­ ↑AP duration)

1B (¯↓ AP duration)

Drugs act mostly on the most active cells, which are usually those driving the arrhythmia.

Class 1 Drugs: Therapeutic Effects

  -increased TP prevents triggering of cells

Subgroups A-C differently affect duration of AP by differently affecting

K+ current.

Subgroup 1A drugs:  ¯¯¯↓↓↓ K+ current ⇒ slows repolarization ⇒ ↑­ AP duration

Subgroup 1B drugs: ↔ K+ current ⇒ does not slow repolarization

Na+ blockade accelerates repolarization ⇒ ¯↓ AP duration

¯↓ K+ current ⇒ slows repolarization a bit

Na+ blockade accelerates repolarization a bit

No net effect

on AP duration.

• automaticity
  
• ↑Potential threshold, ↓Phase 4 depolarization
• Early afterdepolarizations
  
• ↑AP duration (1A only)
• Late afterdepolarizations
  
• ↑Potential threshold
• Re-entry
  
• ¯ ↓Conduction, ↑AP duration (1A only)

• Precipitation of certain types of arrhythmias
  
• Example: Prolongation of AP may have the same effect of early afterdepolarizations.
  
• Anti-arrhythmics commonly have some pro-arrhythmic effects
  

Common adverse effects are related to the drugs anesthetic action:

Precipitation of certain types of arrhythmias

Extension of therapeutic effects:

•¯ ↓ conduction may result in heart block.

Asystole and cardiac arrest

Bronchoconstriction in patients with Asthma

Class-3 drugs block the re-polarizing K+ current, thus   prolonging AP.

• automaticity
  
• None
• Early afterdepolarizations
  
• ↑AP duration
• Late afterdepolarizations
  
• None
• Re-entry
  
• ↑AP duration

Cardiac effects: bradycardia & heart block

  Torsades de pointes (due to AP prolongation)

Other effects: hypotension (due to vasodilation and cardiac effects)

            Pulmonary fibrosis (drug accumulates in lungs)

            Liver dysfunction (hepatic metabolism)

            Hypo- or hyperthyroidism (drug is T3/T4 analog)

  -T3- triodothyronine, T4- thyroxine

Substrate of cytochrome P450 3A4 and moderate inhibitor of isoenzyems (CYP 2D6, 2C9 and 3A4). Inhibits P-glycoprotein.

Blockade of

Ca2+ channels

Verapamil

Drugs act mostly on the most active cells, which are usually those driving the arrhythmia.

Ca2+ block: ­↑ TP 

Ca2+ block: ¯↓ Conductivity

Only verapamil and diltiazem

are antiarrhythmics

• automaticity
  
• Threshold potential
• Early afterdepolarizations
  
• None
• Late afterdepolarizations
  
• Threshold potential
• Re-entry
  
• ¯ Conductivity

Negative inotropic effects (limits use in diseased hearts)

Large doses may cause atrioventricular block