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S2B3: Pharm > Antiarrhythmic Agents > Flashcards

Antiarrhythmic Agents Flashcards

1
Q

Describe the conduction pathway for action potentials in the heart

A
  • Action potential in SA node (normal pacemaker)
  • propagated through the atria where you have atrial contraction
  • The action potential then reaches the AV node where it passes through to the Purkinje fibers at the base of the ventricles
  • Then spreads through the ventricles, producing ventricular contraction
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2
Q

Describe the currents asociated with each phase of the provided action potential

A
  • Sharp, abrupt upstroke depolarization due to influx of sodium through voltage dependent sodium channels (phase 0)
  • brief repolarization (phase 1)
  • sustained depolarization, due to L-type calcium channels (phase 2)
    • triggering calcium release from SR, which then causes the contraction
  • Repolarization cause by an increase in outward potassium current (phase 3)
  • K/Na ATPase (hyperpolarizing exchanger) restores the normal gradient and Na/Ca exchanger (depolarizing exchanger) is removing an excess calcium (phase 4)
    • they usually balance each other
    • their unbalance can cause arrhythmias
  • Effective Refractory Period (ERP) – if in ERP, cell cannot generate another action potential
    • longer ERP: can prevent arrhythmias
    • BUT, if too long can cause arrhythmias
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3
Q

Why is it important that the resting membrane potential in cardiac myocytes lower than in the SA & AV nodes?

A
  • Myocytes
    • Na channels have 2 gates – an activation gate & an inactivation gate
      • phase 4 activation gate is closed, but inactivation gate is open
      • phase 0 hits, the acivation gate opens (b/c so depolarized) & sodium enters to generate the action potential
  • SA & AV nodes
    • Max diastolic potential is so depolarized that the sodium channels are in a perminant inactivation state
      • so, even though they are in the SA & AV nodes, they do not participate in the action potential
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4
Q

Describe the currents associated with each phase of the action potential.

Is this from a myocyte or nodal cell?

A
  • Phase 4 in these cells shows a slow depolarization
    • there is no voltage dependent Na-channels that are generating action ponentials in the SA and AV nodes
  • Upstroke (phase 0) is due completely to L-type calcium channels
  • Repolarization (phase 3) is still due to potassium currents
  • Funny current is activated by hyperpolarization, once you get into phase 4, starts activate If — it is slowly activated over time & this is why you have the gradual depolarization in phase 4
  • The NCX (sodium/calcium exchanger) is depolarizing
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5
Q

What causes arrhythmias?

A
  • Arrhythmia
    • results from disturbances of AP generation, conduction, or both
    • may be supraventricular (involving the atria and/or AV node) or ventricular in origin
    • may involve a rapid heart rate (tachyarrhythmia) or slow heart rate (bradyarrhythmia)
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6
Q

How do we treat bradyarrhythmias?

A

Antiarrhythmic drugs can cause bradyarrhythmias, but cannot treat them. These arrhythmias are usually treated with an implantable device

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7
Q

Mechanisms of Arrhythmias?

A
  • Abnormal impulse generation -1
    1. changes in automaticity
      • altered pacemaker activity (SA or AV nodes)
      • abnormal pacemaker sites (atrial or ventricular cells)
        • can occur in damaged cardiac tissue (post MI)
        • depolarized membrane potential makes AP generation easier
    2. Triggerred activity: impulses generated by afterdepolarizations following a normal AP
      • Phase 2-3 early after depolarization (EAD): prolonged AP duration –> calcium (Cav) channel reactivation durgin repolarization
        • can lead to an additional action potential
      • Phase 4 delayed afterdepolarization (DAD): intracellular Ca2+ overload, NCX depolarizes cardiomycyte to generate DAD –> sodium (Nav) channel reactivation during phase 4
    3. Abnormal impulse conduction
      • conduction block: occurs when impulse propagation fails (e.g. through the AV node or His-Purkinje system)
      • reentry: occurs when an impulse returns and reactivates a previously excited tissue
        • nonuniform conduction in a circuit may result in unidirectional block if the tissue is initially refractory
        • later, an impulse may be conducted int he wrong direction, generating a reentrant arrhythmia
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8
Q

A long QT can lead to what problem?

A

Torsades de Pointes

polymorphic ventricular tachycardia – very deadly

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9
Q

Through which mecnahisms can drugs induce new arrhythmis or worsen existing ones?

A
  • Mechanisms
    • profound slowing of conduction velocity may lead to reentry or heart block (e.g. some Nav channel blockers)
    • increasing AP duration (LQT) may induce Torsades de Pointes, a polymorphic ventricular tachycardia associated with drugs that prolong the QT interval (e.g. some K channel blockers)
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10
Q

What are the 4 Vaughn Williams classifications for antiarrhythmic drugs?

A
  • Class I: sodium channel blockers
    • 3 goups: IA, IB, IC
    • differnet effects on Nav channel kinetics
  • Class II: beta-receptor blockers
  • Class III: Potassium channel blockers (IKr)
  • Class IV: calcium channel blockers

** some drugs may belong to more than one class aof others do not fit into this classification scheme

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11
Q

What are the classification of drugs that treat atrial fibrillation?

A
  • Rate control (slow the AP conduction through the AV node to control the ventricular rate)
    • Class II: Beta-blockers
    • Class IV: Cav channel blockers
  • Rhythm Control (maintain the heart in sinus rhythm)
    • Class I: Nav channel blockers
    • Class III: Kv channel blockers
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12
Q

What categories are use to treat supraventricular tachycardias?

Target of rate contol drugs?

Target of rhythm control drugs?

What categories are used to treatventricular? tachycardias

A
  • Supraventricular tachycardias
    • all classes except IIb
    • Rate control: (target AV node)
      • Class II - beta blockers
      • Class IV - Calcium chanel blockers (ICa-L)
      • Digoxin
    • Rhythm control (targets atria and ventricles)
      • Class I (but not Ib) - Sodium channel blockers (INa)
      • Class III - potassium channel blockers (IKr)
  • Ventricular Tachycardias
    • all classes, but not Ia or Ic if structural damage (e.g. MI)
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13
Q

Describe the mechanism of action for Class I drugs & its subclasses

A
  • Class I will block the voltage dependent Na channels that are generating the AP
    • tend to get a reduce rate of upstroke
    • increae the threshold for AP generation, therefore delay the generation of the next action potential
      • effectively decreasing the maxium heart rate
  • Since there are no voltage dependent Na currents in the SA and AV nodes, – only target myocytes of atria, purkinje fibers & ventricular myocytes
  • IA
    • used for both atrial & ventricular tachycardia
    • extends the QT interval b/c also block K current (class III)
  • IB
    • only used for ventricular tachycardia
    • weakest effect on the upstroke of the AP
    • shorten AP a bit
  • IC
    • used for both atrial & ventricular tachycardia
    • most potent soium channel blockers, but do not extend the length of the AP
      • avoid in patients with structural damage (post-MI) or HF
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14
Q

Name the Class IA, Class IB, and Class IC drugs

A
  • Class IA
    • Quinidine
    • Procainamide (IV only)
    • disopyramide
  • Class IB * CAN be used in patients with a MI or previous MI
    • lidocaine (IV only)
    • mexiletine
  • Class IC – most commonly used
    • flecainide
    • propafenone
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15
Q

What are the general features of Class I drugs?

A
  • Block Sodium (Nav) channels to inhibit Na+ influx
    • fewer active Nav channels
      • longer time to reach AP thrshold
      • slower heart rate
      • suppressed DADs (ectopic pacemaker cells)
    • decreased upstroke velocity (phase 0) and reduced cardiac AP amplitude
      • depressed conduction velocity
      • slowed impulse propagation (strongest for IC)
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16
Q

What are the cardiac effects of Class IA drugs?

A
  • Cardiac effects
    • artial fibrillation: normalize rhythm - Rhythm control
    • antimuscarinic actin
      • enhanced conduction through the AV node
      • High ventricular rates in patients with atrial fibrillation
      • May need to reduce the ventricular rate with a Rate Control drug (slows AV conduction velocity)
        • Class II or IV drug
    • Blockade of IKr channels (Class III effect)
      • prolongs QT interval (delayed AP repolarization)
      • increased risk of Torsades de Pointes
17
Q

Describe the clinical uses, phamacokinetics & adverse effects of Quinidine

A

Quinidine – Class IA agent

  • Original antiarrhythmic drug (first used 1918)
  • uses
    • atrial and ventricular tachyarrhythmias
  • pharmacokinetics
    • readily absorbed orally
    • hepatic metabolism by CYP3A4 but strong CYP2D6 blocker
  • Adverse effects
    • significat toxicity limits use
    • GI: diarrhea, nausea, and vomiting (30-50% patients)
    • cinchonism: headache, dizziness, tinnitus
    • CV: long QT –> Torsades de Pointes
    • thrombocytopenia (rare)
18
Q

Describe the clinical uses, phamacokinetics & adverse effects of Procainamide

A

Procainamide–IV only

  • uses
    • convert atrial or ventricular tachyarrhythmias to sinus rhythm
  • Pharmacokinetics
    • 1/2 life = 3-4 hours
    • metabolism: hepatic acetylation to active metabolite, N-acetylprocainamide (NAPA), which blocks IKr (class III)
    • NAPA long 1/2 life, can accumulate, renal elimination
  • Adverse effects: toxicity limits long-term use
    • hypotension due to ganglionic blockage during infusion
    • GI: diarrhea, nausea, and vomiting (~10% of patients)
    • Lupus-like disorder – arthralgia and arthritis (slow acetylators)
    • CV: LQT –> Torsades de Pointes
19
Q

Describe the clinical uses, phamacokinetics & adverse effects of Dispyramide

A

Disopyramide

  • Uses
    • atrial and ventricular tachyarrhythmias
  • Pharmacokinetics
    • readily absorbed orally
    • 50% excreted renally unchanged
    • 50% CYP3A4 metabolism
  • Adverse effects: not a first-line agent
    • strong anti-muscarinic effect: urinary retention (males), dry mouth, blurred vision, constipation and glaucoma
    • CV: negative inotropic effect (unknown mechanism) - can induce heart failure
    • CV: avoid in heart failure
20
Q

What are the cardiac effects of the Class IB agents?

A
  • Cardiac effects
    • less potent INa block than other class I drugs
      • faster blocking adn unblocking kinetics
    • preferential effect on depolarized cells
      • long AP duration: Purkinje and ventricular cells
      • damaged tissue
    • uses: ventricular arrhythmias only
      • used to treat ventricular arrhythmias in patients with cardiac tissue damage (MI or post-MI)
21
Q

Describe the clinical uses, phamacokinetics & adverse effects of Lidocaine

A

Lidocaine - local anesthetic - IV only

  • Uses:
    • terminate ventricular arrhythmias only
      • but amiodarone is more effective
  • pharmacokinetics
    • IV only, vety stron 1st pass metabolism
    • hepatic metabolism: CYP1A2 adn CYP2A4, reduce dose for patients with liver disease
  • Adverse effects
    • less cardiotoxic than either class IA or IC agents
    • neurological: tremor, blurred vision, and lethargy. An overdose can cause seizures
22
Q

Describe the clinical uses, phamacokinetics & adverse effects of Mexiletine

A

Mexiltine

  • uses
    • ventricular arrhythmias only
      • used for post-MI ventricular arrhythmias, but often given with aother anti-arrhythmic drug (e.g. amiodarone)
  • pharmacokinetics
    • orally acitve version of lidocaine; resists 1st pass metablism
    • hepatic metabolism by CYP1A2 & Cyp2D6
  • adverse effects
    • GI upset
    • neurological: tremor, blurred vision, and lethargy
      *
23
Q

What are the cardiac effects of the Class IC agents?

Clinical uses?

A
  • Higest affinity for blockign sodium channels
    • strongest decrease of the upstroke velocity
    • profound reduction of conduction velocity - can be proarrhythmic
    • no effect on Ap repolarization
  • uses
    • supraventricular arrhythmias - rhythm control
    • prevent reoccurence of ventricular tachycardia
    • only used in patients without heart disease
      • not used in post MI or heart failure patients
24
Q

Why are class III drugs not used in patients with a past MI or heart failure?

A
  • Damage to the heart can creat a place where the AP is obstructed or extinguished
  • b/c class III so strongly slow the propagation of the AP through the ventricles, these reentry arrhythmias can be much more common in these particular individuals
  • Mechanism of reentry
    1. there must be an ovstacle (anatomic or physiologic) to homogenous conduction
    2. there must be unidirection block at some point in the circuit
    3. the conduction speed must be slow enough to allow sufficient time for the tissue to recover from the previous action potential
25
Q

Describe the clinical uses, phamacokinetics & adverse effects of Flecainide

A

Flecainide

  • ​Uses
    • supreventricular and ventricular tachycardia
      • contraindicatedin patients with previous MI or HF
  • pharmacokinetics
    • good oral availability
    • metabolized by CYP2D6 and renal clearance 30% as parent drug (i.e. unmetabolized)
    • 1/2 life greately increased in patients with renal disease
  • adverse effects
    • neurologic - dizziness, blurred vision, tremor, headache
    • CV: bradycardia, heart block, ventricular arrhythmias, HF
26
Q

Describe the clinical uses, phamacokinetics & adverse effects of Propafenone

A

Propafenone -

also blocks cardiac B-adrenergic receptors (Class II)

  • uses
    • supraventricular and ventricular tachycardias
      • contraindicated in patients with previous MI or HF
  • pharmacokinetics
    • good oral availability
    • metabolized by CYP2D6 adn excreted via the liver
  • adverse effects
    • same as flecainide
    • metallic taste
    • bronchospasm - nonselective beta-adrenergic receptor block

S2B3: Pharm (3 decks)

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