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12. Pharmacology > Anti arrhythmics > Flashcards

Anti arrhythmics Flashcards

1
Q

Vaughn Williams scheme classification

A

classify drugs according to their primary electrophysiologic action/ability to block channels

Class I-V

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2
Q

Vaughn Williams scheme limitations

A

 Many anti arrhythmic agents have multiple action mechanisms
 No consideration of drug metabolites effects
 Antiarrhythmic effect based on channel blockers → no channel activation
 Based on action on normal tissues vs diseased

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3
Q

Sicilian gambit

A

How drug affect ionic current, R, pumps
o Vulnerable parameter to target to abolish the arrhythmia

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4
Q

Class I: MOA

A

Na+ channel blockers
* ↓ Na+ flux → depress phase 0 of action potential
* Membrane stabilizers

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5
Q

Class I subgroups classification based on

A

based on ability to slow conduction and alter AP: variable blocking effect (+)

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6
Q

Class Ia: drugs

A

Quinidine, Procainamide

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7
Q

Class Ia: blocking ability

A

++

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8
Q

Class Ia: effects on AP

A
  • ↓phase 0 and conduction velocity
  • Prolong AP duration
    o ↑ effective refractory period
  • Delay repolarization → mild class III action
    o Block some K+ channels
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9
Q

Class Ib: drugs

A

Lidocaine, Mexiletine, Tocainide, Phenytoin (Lettuce, Tomato, Mayo, Please!)

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10
Q

Class Ib: effects on AP

A
  • Little to no effect on phase 0 or conduction velocity in normal tissue
    o Will ↓ in diseased tissue
  • ↓AP duration
    o ↑ effective refractory period
  • ↑ ventricular fibrillation threshold
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11
Q

Class Ib: blocking ability

A

+

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12
Q

Class Ic: blocking ability

A

+++

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13
Q

Class Ic: drugs

A

Morcizine, Flecainide, propafenone

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14
Q

Class Ic: effects on AP

A
  • Marked depression in phase 0 and conduction velocity
  • Minimal effects on repolarization and refractoriness
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15
Q

Class II: MOA

A

Beta blockers
Anti sympathetic/sympatholytic effects → prevent effects of catecholamines on the heart

  • Antiarrhythmic effect: β1-adrenoreceptor blockade
    o Can also affect α1-R depending on drug
    o α1-R stimulation may be important in arrhythmias related to ischemia or drugs
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16
Q

Class II: drugs

A

Atenolol, esmolol, propranolol, metoprolol, timolol, bisoprolol

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17
Q

Class II: effect on AP

A

o Depress sinus node automaticity
 - inotrope & chronotope
 - dromotrope
o ↓ slope of phase 4 depolarization
 ↓ current If = important pacemaker current
* Promotes proarrhythmic depolarization in damaged heart tissue
o Inhibits inward Ca2+ current ICa-L
 Indirectly inhibited by fall in AMPc levels
 Ca2+ dependant triggered arrhythmias
o Slow down AV node conduction; not really a direct anti arrhythmic effect
 Prolong repolarization → ↑ PR

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18
Q

Class III MOA

A

K+ channel blockers

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19
Q

Class III drugs

A

Amiodarone, Sotalol, Ibutilide, Dofetilide, Dronedarone

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20
Q

Class III effects on AP

A
  • ↑ AP duration → prolong phase 3 of repolarization
    o Delayed repolarization
    o W/o affecting rate of phase 0 or conduction velocity
    o Some can have Na+ channel blocking effects
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21
Q

Class IV drugs

A

Diltiazem, Verapamil (cardiac), Amlodipine (Vascular)

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22
Q

Class IV MOA

A

o Block L-type Ca2+channels
o Important ion to maintain normal automaticity and conduction in SA/AV nodes
 - chronotrope and dromotrope

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23
Q

What types of arrhythmias controlled by class IV

A

SVT

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24
Q

Class IV effect on AP

A

o Cardiomyocytes: shorten phase 2
o Nodal cells
 ↓ slopes of phase 0, 3 and 4
 Prolonged repolarization via AV node (phase 3

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25
Q

What determines selectivity of class IV to cardiac tissue

A

o Depend on specific binding site on channel
 Dihydropyridines: selective for vascular smooth muscle cell
* Amlodipine
* Indication for systemic hypertension
 Non-dihydropyridines: cardio selective
* Diltiazem and Verapamil

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26
Q

Class V drugs

A

Others
Digoxin
Class IV-like – K+ channel opener = Adenosine
Magnesium sulfate

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27
Q

Adenosine MOA

A
  • Causes cell hyperpolarization
    o Stimulates A1-Receptor on atrium, SA/AV node → opening adenosine sensitive K+ channel → hyperpolarize and inhibit AV node → hyperpolarization inhibit Ca2+ channels
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28
Q

Adenosine effect on AP

A
  • ↓ automaticity, conduction velocity
  • ↑ refractory period
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29
Q

Digoxin MOA

A
  • Blocks Na+/K+ exchanger
    o ↑ intra¢ Na+ → activate Na+/Ca2+ exchanger to pump out Na+ in exchange for Ca2+ → ↑ intra¢ Ca2+
  • ↑ myocardial contractility
  • Stimulates p∑ system = ↑ activity of vagal nerve
    o ↓ SN discharge rate
    o ↓ conduction through AV node
    o → Negative chronotrope
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30
Q

Mg sulfate MOA

A
  • Transport of Na, K, Ca
  • Precise mechanism for arrhythmia unknown
    o Weakly blocks Ca2+ channel
    o Inhibits K+ and Na+ channels
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31
Q

Sicilian gambit classification

A

based on modification of vulnerable parameter

↓ phase 4 of depolarization
↓ AP duration/suppress EADs
Ca2+ overload/suppress DADs
↓conduction/excitability
↑refractory period

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32
Q

Sicilian gambit: ↓ phase 4 of depolarization
-MOA
-Arrhythmias
-Drugs

A
  • Mechanism: enhanced automaticity
  • Arrhythmias
    o Inappropriate sinus tachycardia
    o Idiopathic ventricular tachycardia
    o AIVR
  • Drugs
    o β-blockers
    o Na+ channel blockers
    o Ca2+ channel blockers
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33
Q

Sicilian gambit: ↓ AP duration/suppress EADs
-MOA
-Arrhythmias
-Drugs

A
  • Mechanism: triggered activity
  • Arrhythmias: Torsades de Pointes
  • Drugs:
    o β-agonists or blockers
    o Ca2+ channel blocker
34
Q

Sicilian gambit: Ca2+ overload/suppress DADs
-MOA
-Arrhythmias
-Drugs

A
  • Mechanism: triggered activity
  • Arrhythmias:
    o Digitalis induced ventricular arrhythmia.
    o Autonomically mediated Vtach
  • Drugs
    o Ca2+ channel blockers
    o β-blockers
    o Na+ channel blockers
35
Q

Sicilian gambit: ↓conduction/excitability
-MOA
-Arrhythmias
-Drugs

A
  • Arrhythmias:
    o Sustained monomorphic Vtach
    o AV nodal re-entrant tachycardia
  • Drugs
    o Na+ channel blockers
    o Ca2+ channel blockers
36
Q

Sicilian gambit: ↑refractory period
-MOA
-Arrhythmias
-Drugs

A
  • Arrhythmias
    o Polymorphic and sustained monomorphic Vtach
    o Ventricular fibrillation
  • Drugs
    o K+ channel blockers
    o Na+ channel blockers, class Ia
37
Q

Use dependence: definition

A

↑ efficacy after repeated use on tissue
o ↑ anti arrhythmic effect at ↑HR
o Desirable anti arrhythmic drug quality

38
Q

What determines the use dependence of a drug

A
  • Onset/offset kinetics of the drug
    o Association and dissociation time constant
     Time for drug to bind/unbind to its receptor
     Major differences btw class I anti arrhythmics (Ia, Ib, Ic)
39
Q

Why drugs w/ use dependency works better w/ incr HR

A

o Tachycardia → ↓ diastole
 Inactivated state cell > activated state
 Drug binding during inactive state = ↑ anti arrhythmic effect

o Rapid offset kinetic: build up on channel receptor during rapid Vtach
 ↑ anti arrhythmic effect with shorter coupling interval
 ↑ drug binding and ↓ unbinding

40
Q

Class Ia vs Ib: use dependency

A

Class Ia: use dependent at slower rates (vs Ib)
* Slower recovery from block

Class Ib: determinants of drug binding
* HR (use dependency)
* Depolarized cell → higher resting potential
o Promote inactivated state
o Partially depolarized cell are usually diseased and initiator of arrhythmias
* ↓pH and ↑extra cell [K+] → present in diseased myocardium

41
Q

Reverse use-dependence: definition

A

↓ anti arrhythmic effect at ↑HR
o Prolongation of AP duration → greatest effect at slower HR
o Undesirable characteristic → ↓ effectiveness of anti arrhythmic at faster HR
 More effective to prevent tachyarrhythmia than converting back to sinus rhythm
 Not as effective in acute management of arrhythmia to convert back to sinus rhythm

42
Q

Which class has reverse use-dependence properties

A
  • Class III anti arrhythmic
    o Most drugs block Ikr (delayed rectifier K+ current)
     Maximal prolongation of AP and refractoriness
    o Amiodarone → prolong AP at equivalent degree at lower or higher HR
     Not reverse dependent effect
     May explain lower incidence of torsade de Pointes vs sotalol
     Also block Ik-ATP (ATP sensitive K+ channel)
43
Q

Properties of lidocaine

A
  • Slows conduction
  • ↓ dispersion of refractoriness
  • ↓ action potential duration
  • ↑ effective refractory period
  • ↓ rate of phase 4 depolarization
44
Q

Lidocaine: slow conduction MOA

A

o Na+ channel blockade
 Lidocaine will bind → block Na+ channel when inactivated
o Potential difference btw depol and nondepol cells
 ↑ potential difference →↑ gradient propagating the wave
 Lidocaine ↓ potential difference → slow conduction
* Can change unidirectional to bidirectional block and stop re-entry

45
Q

Lidocaine: decr dispersion of refractoriness MOA

A

o Dz myocytes: variable AP duration and refractoriness → promote re-entry and unidirectional block
o Lidocaine ↓ AP duration → ↑ effective refractory period → ↓ dispersion
 ↑ uniformity of refractoriness
 ↓ likelihood of bidirectional block

46
Q

Lidocaine: decr AP duration MOA

A

o Dz/drugs can ↑ AP duration
 EADs → ventricular arrhythmias
 Can be inhibited with AP shortening

47
Q

Lidocaine: incr effective RP MOA

A

o Post repolarization refractoriness
 Myocyte remain refractory (grey area in figure)
 Bidirectional block
o Inhibit arrhythmias from enhanced abnormal automaticity or re-entry

48
Q

Lidocaine: decr rate of phase depol MOA

A

o Inhibition of spontaneous depol → ↓ automatic arrhythmias

49
Q

Class Ia: effect of AP upstroke and conduction velocity

A
  • Moderate effect
    o ↓phase 0 and conduction velocity
50
Q

Class Ib: effect of AP upstroke and conduction velocity

A
  • Little to no effect on phase 0 or conduction velocity in normal tissue
    o Will ↓ in diseased tissue: selectively act on ischemic/diseased tissues
     Promote conduction block → interrupt re-entry
51
Q

Class Ic: effect of AP upstroke and conduction velocity

A

o Powerful inhibitors of Na+ channels
 Marked depression in phase 0 and conduction velocity
 Inhibition of His-Purkinje conduction → QRS widemning

52
Q

Class Ia: effect of AP duration

A
  • Prolong AP duration
    o ↑ effective refractory period
    o Delay repolarization → mild class III action
     Block some K+ channels
53
Q

Class Ib: effect of AP duration

A
  • ↓AP duration
    o ↑ effective refractory period
  • ↑ ventricular fibrillation threshold
54
Q

Class Ic: effect of AP duration

A

o AP prolongation
 Delay inactivation of slow Na+ channels
 Inhibition of rapid repolarizing current Ikr
o Minimal effects on repolarization and refractoriness

55
Q

Class Ia: effect on AV node

A

o Quinidine accelerates conduction (anticholinergic)
o Procainamide: dose dependent
 Low: ↑ conduction
 High: ↓ conduction

56
Q

Class Ib: effect on AV node

A

little effect

57
Q

Class Ic: effect on AV node

A

↓ conduction

58
Q

Class Ia: effect on accessory pathway

A

↑ refractory period of accessory pathway

59
Q

Class Ib: effect on accessory pathway

A

no effect

60
Q

Class Ic: effect on accessory pathway

A

o ↑ ante/retrograde conduction time
o ↑ refractoriness

61
Q

Quinidine: anti arrhythmic effect depend on

A
  • Direct and indirect action from competitive blockade of muscarinic cholinergic R
    o Anti arrhythmic effect depend on p∑ tone
    o p∑ system innervate SA node and AV conduction
     Quinidine may ↑ SA automaticity and AV conduction
     Important if treating Afib/flutter →may ↑ ventricular response
62
Q

Effects of serum K+ on quinidine effect

A
  • ↓ serum [K+] → antagonize quinidine effect
  • ↑ serum [K+] → ↑ effects → ↓ conduction velocity, membrane responsiveness and automaticity
63
Q

ECG quinidine

A
  • ↑ sinus rate (minimal to moderate)
  • Slight ↑QRS duration
    o If >25% → indicative of toxicity
  • QT prolongation
  • Normal PR
64
Q

PharmakoK quinidine

A
  • Lipophilic weak base, rapidly distributed in peripheral tissues
    o Bound to plasma/tissue proteins
    o Large distribution volume
  • Elimination: kidneys
  • Metabolized by liver
  • Can compete for tissue binding sites with certain drugs
    o Digoxin
65
Q

Side effects quinidine

A

nausea, vomiting, diarrhea in 25% of dogs

66
Q

Toxicity quinidine

A

o Negative inotrope
o Vasodilation
o Hypotension
o 1st, 2nd, 3rd degree AVB, intraventricular block, Vtach

67
Q

Procainamide: action of ventricular and atrial tissue

A

o Atrial > ventricular automatic tissues more sensitive
o Effect on automaticity = primary anti arrhythmic effect
 ↓ rate of rise of phase 0 → ↓ conduction velocity in all cardiac tissues

68
Q

Procainamide: effect of dose on action

A
  • Similar to quinidine, direct and indirect anticholinergic actions
    o Low dose: vagolytic action
    o High dose: direct depressant effect

o Prolonged AV nodal/His Purkinje conduction
 No effect/little when normal sinus rhythm
o ↑ refractory period of atrial and ventricular muscles

69
Q

Procainamide: Pharmacokinetics

A
  • Lipophilic weak base, rapidly distributed in peripheral tissues
    o Bound to plasma/tissue proteins
    o Large distribution volume
  • Elimination: kidneys
    o Renal excretion α to creatinine clearance
  • Metabolized by liver
70
Q

Side effects procainamide

A
  • Minimal cardiovascular depressant effects compared to quinidine
71
Q

Procainamide tox

A

o Toxic dosage:
 Hypotension
 Marked ↓ in AV conduction
o 1st, 2nd, 3rd degree AVB can occur

72
Q

drug of choice for acute management of ventricular arrhythmias and why

A

Lidocaine

o Affinity for inactivated Na+ channels
o Rapid onset/offset kinetics

  • Little effect on sinus rate, conduction, AP duration or refractoriness
    o No anticholinergic effects
    o No effect on SVTs
73
Q

Serum K+ effect on lidocaine

A
  • Effect depend on [K+] → hyper K+ = ↑ effect
74
Q

Lidocaine pharmacoK

A
  • Lipophilic weak base, rapidly distributed to extravascular tissues
    o Large distribution volume
    o Binds to plasma proteins
  • Hepatic metabolism: 1st pass effect
    o Rapidly metabolized by liver: depend on
     Liver blood flow → CHF, propanolol and cimetidine can predispose to toxicity
     Liver microsomal activity (enzyme inducers): ↑ dose with barbiturates/phenytoin
    o Repeated doses of infusion necessary to maintain therapeutic levels
  • ↑[Metabolites] in circulation
    o May contribute to toxic/therapeutic effects
75
Q

Lidocaine dosage

A

o Loading doses: 2x IV bolus 30 min apart followed by CRI
o After infusion → ½ life may be up to 24h
 Redistribution from poorly perfused tissues

76
Q

Lidocaine side effects/tox

A
  • Minimal ↓ in cardiac contractility
  • Central nervous system excitement → most common
    o Agitation, disorientation, muscle twitching, nystagmus
    o Generalized tonic-clinic seizures
    o Cats more sensitive > dogs
  • Drowsiness, depression
77
Q

Mexiletine indications

A
  • Indicated for ventricular arrhythmias
78
Q

Mexiletine combo

A
  • Can be combined to β-blockers
    o ↑ effectiveness + ↓ side effects
79
Q

Mexiletine side effects/tox

A
  • Anxiety, depression
  • Twitching
  • GI adverse effect in ⅓ of dogs: often sotalol will be tolerated better
80
Q

Class Ic: 3 major electrophysiologic effects

A

o Powerful inhibitors of Na+ channels
 Marked depression in phase 0 and conduction velocity
 Inhibition of His-Purkinje conduction → QRS widemning

o AP prolongation
 Delay inactivation of slow Na+ channels
 Inhibition of rapid repolarizing current Ikr

o Minimal effects on repolarization and refractoriness

81
Q

Class Ic: Proarrhythmic effects

A

o Faster HR
o ↑ ∑ activity
o Diseased, ischemic myocardium → avoid in structural heart dz

82
Q

Class Ic: effective for

A

o Paroxysmal SVTs, refractory ventricular arrhythmias
o Catecholaminergic polymorphic Vtach
 RyR2 channel blockade

12. Pharmacology (10 decks)

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