Anti arrhythmics Flashcards
Vaughn Williams scheme classification
classify drugs according to their primary electrophysiologic action/ability to block channels
Class I-V
Vaughn Williams scheme limitations
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
Sicilian gambit
How drug affect ionic current, R, pumps
o Vulnerable parameter to target to abolish the arrhythmia
Class I: MOA
Na+ channel blockers
* ↓ Na+ flux → depress phase 0 of action potential
* Membrane stabilizers
Class I subgroups classification based on
based on ability to slow conduction and alter AP: variable blocking effect (+)
Class Ia: drugs
Quinidine, Procainamide
Class Ia: blocking ability
++
Class Ia: effects on AP
- ↓phase 0 and conduction velocity
- Prolong AP duration
o ↑ effective refractory period - Delay repolarization → mild class III action
o Block some K+ channels
Class Ib: drugs
Lidocaine, Mexiletine, Tocainide, Phenytoin (Lettuce, Tomato, Mayo, Please!)
Class Ib: effects on AP
- 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
Class Ib: blocking ability
+
Class Ic: blocking ability
+++
Class Ic: drugs
Morcizine, Flecainide, propafenone
Class Ic: effects on AP
- Marked depression in phase 0 and conduction velocity
- Minimal effects on repolarization and refractoriness
Class II: MOA
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
Class II: drugs
Atenolol, esmolol, propranolol, metoprolol, timolol, bisoprolol
Class II: effect on AP
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
Class III MOA
K+ channel blockers
Class III drugs
Amiodarone, Sotalol, Ibutilide, Dofetilide, Dronedarone
Class III effects on AP
- ↑ 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
Class IV drugs
Diltiazem, Verapamil (cardiac), Amlodipine (Vascular)
Class IV MOA
o Block L-type Ca2+channels
o Important ion to maintain normal automaticity and conduction in SA/AV nodes
- chronotrope and dromotrope
What types of arrhythmias controlled by class IV
SVT
Class IV effect on AP
o Cardiomyocytes: shorten phase 2
o Nodal cells
↓ slopes of phase 0, 3 and 4
Prolonged repolarization via AV node (phase 3
What determines selectivity of class IV to cardiac tissue
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
Class V drugs
Others
Digoxin
Class IV-like – K+ channel opener = Adenosine
Magnesium sulfate
Adenosine MOA
- 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
Adenosine effect on AP
- ↓ automaticity, conduction velocity
- ↑ refractory period
Digoxin MOA
- 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
Mg sulfate MOA
- Transport of Na, K, Ca
- Precise mechanism for arrhythmia unknown
o Weakly blocks Ca2+ channel
o Inhibits K+ and Na+ channels
Sicilian gambit classification
based on modification of vulnerable parameter
↓ phase 4 of depolarization
↓ AP duration/suppress EADs
Ca2+ overload/suppress DADs
↓conduction/excitability
↑refractory period
Sicilian gambit: ↓ phase 4 of depolarization
-MOA
-Arrhythmias
-Drugs
- 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
Sicilian gambit: ↓ AP duration/suppress EADs
-MOA
-Arrhythmias
-Drugs
- Mechanism: triggered activity
- Arrhythmias: Torsades de Pointes
- Drugs:
o β-agonists or blockers
o Ca2+ channel blocker
Sicilian gambit: Ca2+ overload/suppress DADs
-MOA
-Arrhythmias
-Drugs
- 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
Sicilian gambit: ↓conduction/excitability
-MOA
-Arrhythmias
-Drugs
- Arrhythmias:
o Sustained monomorphic Vtach
o AV nodal re-entrant tachycardia - Drugs
o Na+ channel blockers
o Ca2+ channel blockers
Sicilian gambit: ↑refractory period
-MOA
-Arrhythmias
-Drugs
- Arrhythmias
o Polymorphic and sustained monomorphic Vtach
o Ventricular fibrillation - Drugs
o K+ channel blockers
o Na+ channel blockers, class Ia
Use dependence: definition
↑ efficacy after repeated use on tissue
o ↑ anti arrhythmic effect at ↑HR
o Desirable anti arrhythmic drug quality
What determines the use dependence of a drug
- 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)
Why drugs w/ use dependency works better w/ incr HR
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
Class Ia vs Ib: use dependency
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
Reverse use-dependence: definition
↓ 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
Which class has reverse use-dependence properties
- 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)
Properties of lidocaine
- Slows conduction
- ↓ dispersion of refractoriness
- ↓ action potential duration
- ↑ effective refractory period
- ↓ rate of phase 4 depolarization
Lidocaine: slow conduction MOA
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
Lidocaine: decr dispersion of refractoriness MOA
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
Lidocaine: decr AP duration MOA
o Dz/drugs can ↑ AP duration
EADs → ventricular arrhythmias
Can be inhibited with AP shortening
Lidocaine: incr effective RP MOA
o Post repolarization refractoriness
Myocyte remain refractory (grey area in figure)
Bidirectional block
o Inhibit arrhythmias from enhanced abnormal automaticity or re-entry
Lidocaine: decr rate of phase depol MOA
o Inhibition of spontaneous depol → ↓ automatic arrhythmias
Class Ia: effect of AP upstroke and conduction velocity
- Moderate effect
o ↓phase 0 and conduction velocity
Class Ib: effect of AP upstroke and conduction velocity
- 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
Class Ic: effect of AP upstroke and conduction velocity
o Powerful inhibitors of Na+ channels
Marked depression in phase 0 and conduction velocity
Inhibition of His-Purkinje conduction → QRS widemning
Class Ia: effect of AP duration
- Prolong AP duration
o ↑ effective refractory period
o Delay repolarization → mild class III action
Block some K+ channels
Class Ib: effect of AP duration
- ↓AP duration
o ↑ effective refractory period - ↑ ventricular fibrillation threshold
Class Ic: effect of AP duration
o AP prolongation
Delay inactivation of slow Na+ channels
Inhibition of rapid repolarizing current Ikr
o Minimal effects on repolarization and refractoriness
Class Ia: effect on AV node
o Quinidine accelerates conduction (anticholinergic)
o Procainamide: dose dependent
Low: ↑ conduction
High: ↓ conduction
Class Ib: effect on AV node
little effect
Class Ic: effect on AV node
↓ conduction
Class Ia: effect on accessory pathway
↑ refractory period of accessory pathway
Class Ib: effect on accessory pathway
no effect
Class Ic: effect on accessory pathway
o ↑ ante/retrograde conduction time
o ↑ refractoriness
Quinidine: anti arrhythmic effect depend on
- 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
Effects of serum K+ on quinidine effect
- ↓ serum [K+] → antagonize quinidine effect
- ↑ serum [K+] → ↑ effects → ↓ conduction velocity, membrane responsiveness and automaticity
ECG quinidine
- ↑ sinus rate (minimal to moderate)
- Slight ↑QRS duration
o If >25% → indicative of toxicity - QT prolongation
- Normal PR
PharmakoK quinidine
- 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
Side effects quinidine
nausea, vomiting, diarrhea in 25% of dogs
Toxicity quinidine
o Negative inotrope
o Vasodilation
o Hypotension
o 1st, 2nd, 3rd degree AVB, intraventricular block, Vtach
Procainamide: action of ventricular and atrial tissue
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
Procainamide: effect of dose on action
- 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
Procainamide: Pharmacokinetics
- 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
Side effects procainamide
- Minimal cardiovascular depressant effects compared to quinidine
Procainamide tox
o Toxic dosage:
Hypotension
Marked ↓ in AV conduction
o 1st, 2nd, 3rd degree AVB can occur
drug of choice for acute management of ventricular arrhythmias and why
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
Serum K+ effect on lidocaine
- Effect depend on [K+] → hyper K+ = ↑ effect
Lidocaine pharmacoK
- 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
Lidocaine dosage
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
Lidocaine side effects/tox
- 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
Mexiletine indications
- Indicated for ventricular arrhythmias
Mexiletine combo
- Can be combined to β-blockers
o ↑ effectiveness + ↓ side effects
Mexiletine side effects/tox
- Anxiety, depression
- Twitching
- GI adverse effect in ⅓ of dogs: often sotalol will be tolerated better
Class Ic: 3 major electrophysiologic effects
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
Class Ic: Proarrhythmic effects
o Faster HR
o ↑ ∑ activity
o Diseased, ischemic myocardium → avoid in structural heart dz
Class Ic: effective for
o Paroxysmal SVTs, refractory ventricular arrhythmias
o Catecholaminergic polymorphic Vtach
RyR2 channel blockade
