L22, L24- Antiarrhythmic Drugs Flashcards
describe the action of each phase in a Myocardial Action Potential
Phase 0: Na+ influx (fast), depolarization
Phase 1: K+ efflux, initial repolarzation
Phase 2: K+ efflux, Ca influx, plateau phase
Phase 3: K+ efflux, repolarizaition
Phase 4: resting potential, slow increasing depolarization due to increasing Na+ permeability/influx
most antiarrhythmic drugs target phase ___ of myocardial action potential
phase 3- K+ efflux
describe the action of each phase in a Pacemaker Action Potential
Phase 0: depolarization, Ca influx
Phase 3: repolarization, K+ efflux
Phase 4: resting potential with increasing depolarization due to If channels: mixed Na/K inward current
in terms of action potentials:
P wave = (1)
QRS = (2)
T wave = (3)
1- atrial depolarization
2- ventricular depolarization
3- ventricular repolarization
in terms of EKG, antiarrhythmic drugs acting on:
- Atria affects (1) on EKG
- Ventricle affects (2) on EKG
1- PR interval
2- QT interval
arrhythmias are a result of disturbances in (1), (2), (3)
- impulse formation
- impulse conduction
- or combination of both
list the 4 results on the heart of cardiac arrhythmias
- bradycardia (beat too slowly)
- tachycardia (beat too fast)
- sinus tachycardia / bradycardia (beats regularly)
- AFib (beats irregularly)
arrhythmias are classified as (1) or (2)
- supraventricular (atrial or AV junction)
- ventricular
list the factors that can precipitate arrhythmias (essentially 3 categories)
- ischemia, hypoxia
- acidosis/alkalosis, electrolyte abnormalities
- excessive catecholamine exposure, ANS influences
- DRUG toxicities (especially antiarrhythmics)
list the 4 common causes of arrhthymias
- Abnormal Automaticity
- Afterdepolarizations
(defects in impulse conduction)
- re-entrant circuits
- accessory tract pathways
(1) is where a cardiac site or sites have enhanced automaticity that compete with (2) to generate an arrhthymia
1- abnormal automaticity
2- SA node
To treat abnormal automaticity, drugs usually target (1) and or (2) [include brief effect], in order to achieve (3) overall
1- Phase 4 depolarization: decreases the slope
2- raise threshold of discharge (to less negative voltage)
3- dec in discharge frequency
Normal impulse conduction occurs through a (1) pathway to stimulate entire ventricular surface. In Re-entrant circuits there is a (2), causing (3).
1- bifurcated pathways
2- unidirectional block
3- abnormal retrograde conduction through blocked pathway via anterograde conduction through the unblocked pathway
_____ is the most common cause of arrhthymias
re-entrant circuits
To treat Re-entrant circuits drugs will usually (1) and or (2) in order to cause (3).
1- slow conduction
2- inc refractory period
3- convert unidirectional block into bidirectional block
(1) is when a normal action potential triggers extra, abnormal depolarizations / oscillations to cause arrhthymia. It comes as a (2) or (3) type.
1- afterdepolarizations
2- early
3- delayed
Early-afterdepolarization occur during (1) and are triggered by (2).
Delayed afterdepolarizations occur during (3) due to a (4) mechanism
1- phase 2, 3 / during inciting action potential
2- conditions that prolong action potentials (i.e. drugs that prolong QT interval)
3- end of phase 3 (close to phase 4) / shortly after repolarization
4- unknown, not well understood mechanism
To treat Afterdepolarizations drugs will usually (1) and or (2) in order to (3).
1- slow conduction
2- inc refractory period
3- make cells less excitable
_____ is a common accessory tract pathway
Bypass tract / Bundle of Kent: skips AV node and Bundle of His and goes directly to ventricular wall
The goal of antiarrhythmic therapies are (1) and (2) while using (3), (4), (5) as the guiding principles
1- terminate existing arrhthymia
2- prevent recurrent arrhthymia
3- eliminate, minimize precipitating factors
4- define precise arrhthymia type
5- most antiarrhthymics cause arrhthymia (minimize drug risks)
list the therapies for tachyarrhthymias
- antiarrhthymic drugs
- external electrical cardioversion
- ablation of arrhthymic pathways and implantable cardioverter-defibrillators (increasing in role)
list the therapies for bradyarrhthymia
- **cardiac pacing (Tx if choice)
- Atropine, sympathomimetrics can be used
what are the non-pharmacological therapies for arrhthymias
- pacemakers
- cardioversion
- catheter ablation
- surgery
list the classes of antiarrhthymic drugs
Class I: fast Na channel blockers (phase 0)
Class II: β-blockers (Ca)
Class III: K channel blockers (phase 1, 2, 3*), inhibit repolarization
Class IV: Ca channel blockers (phase 2)
Miscellaneous
Note- phases are for myocardial not nodal APs
list the class I arrhthymia drugs
(fast Na channel blockers)
I-A: quinidine, procainamide, disopyramide
I-B: lidocaine, mexiletine
I-C: flecainide, propafenone
list the popular class II arrhthymia drugs
(β-blockers)
propanolol, metoprolol, esmolol
list the class III arrhthymia drugs
(K channel blockers)
amiodarone, sotalol, dofetilide
list the popular class IV arrhthymia drugs
(Ca channel blockers)
verapamil, dilitiazem (non-dihydropyridines)
list the miscellaneous arrhthymia drugs
digoxin, adenosine, Mg, atropine
Class I arrhthymia drugs act to inhibit (1) so that (2) decreases and phase (3) is delayed. This will overall have a (4) effect on excitability and conduction velocity.
1- fast inward Na+ channels
2- Na influx
3- phase 0, delayed depolarization
4- dec excitability and conduction velocity
describe the Use/State dependence of class I arrhthymia drugs
- does it bind more rapidly to open or inactivated Na channels
- it will effect tissues with more frequent depolarization (i.e. ventricles > atria > nodes)
**cells discharging abnormally high frequency are preferentially blocked
Class I-A drugs include (1). They act to slow (2) and prolong (3). They have a (4) relationship with the state of Na channels.
1- quinidine, procainamide, disopyramide
2- slow rate of change of Phase 0 (Na channel inhibition)
3- prolong Phase 3 (K channel inhibition)
4- intermediate speed of association with activated/inactivated Na channels and intermediate rate of dissociation
Quinidine is a class (1- include mechanism) antiarrhthymic drug. It is used for (2), but it is limited because of (3).
1- I-A, Na channel blocker (+ K channel blocker, class III) 2- supraventricular and ventricular arrhthymia suppression 3- lots of toxicity, replaced by more effective and safer drugs (Ca channel blockers)
Quinidine is administered in (1) fashion therefore (2) can form, although it is known to inhibit (3) also.
1- oral (rapid absorption)
2- CYP3A4 conversion to active metabolite
3- CYP-2D6/3A4 and P-glycoprotein
adverse effects of quinidine
*cinchonism (blurred vision, tinnitus, HA, psychosis)
-arrhthymia (torsades de pointes), SA/AV block, asystole
-n/v/d
-thrombocytopenc purpura
Toxic doses: ventricular tachycardia (exacerbated by hyperkalemia)
Note- also a proarrhythmic
Quinidine contraindications
NOT used in: complete heart block
Caution with:
- prolonged QT syndrome
- h/o tosades de pointes
- incomplete heart block
- uncompensated HF
- myocarditis
- severe myocardial damage
Procainamide is a class (1) antiarrhthymic drug with (2) as its MOAs. It is used for (3), but it is limited because of (4).
1- I-A
2- Na channel blocker (active state), K channel blocker, antimuscarinic
3- supraventricular and ventricular arrhythmia suppression
4- proarrhythmic effects, it is limited to life-threatening arrhythmias
Procainamide is administered in (1) fashion. It will be metablized by (2) into (3), which will have (4) effects.
1- IV
2- CYP2D6 (acetylation)
3- N-acetylprocainamide (NAPA)
4- prolong duration of action potential (class III)
list the adverse effects of procainamide
-chronic use => high chance for AEs
- **reversible lupus-like syndrome (25-30%)
- Toxic doses: asystole, ventricular arrhythmia
- CNS: depression, hallucinations, psychosis
- hypotension
- weak anti-ACh effects
list the contraindications for procainamide
- hypersensitivity
- complete heart block, 2nd degree AV block
- SLE
- torsades de pointes
- HTN, HF (use w/ caution)
Disopramide is a class (1) antiarrhthymic drug with (2) as its MOAs. It is used for (3).
1- I-A
2- neg. ionotropic effects, antimuscarinic, peripheral vasoconstriction, blocks K channels
3- supraventricular and ventricular arrhythmia suppression
list the adverse effects of disopyramide
- neg. ionotropic effects
- severe antimuscarinic effects: xerostomia, urinary retention, blurred vision, constipation
- possible hypotension, cardiac failure
The main Class I-B antiarrhythmic drugs are (1). They will rapidly bind and dissociate from (2) channels. They act to slow (3) phase, decrease slope of (4) phase, and shorten (5) phase. Because of these actions they are best suited to act on (6).
1- lidocaine, mexiletine 2- Na channels 3- phase 0 (depol.) 4- phase 4 (resting) 5- phase 3 (repol.) 6- fast conductors, ventricular tissue
Lidocaine is a class (1- include MOA) type antiarrhythmic drug. It mostly used to treat (2) and is more effective in (3) tissue. It is administered in (4) fashion.
1- I-B, Na channel blocker
2- ventricular arrhythmias
3- ischemic/dead tissue
4- IV due to extensive 1st pass metabolism
list the uses for lidocaine
- local anesthetic
- acute Tx for ventricular arrhythmias from MI or cardiac manipulation/surgery
- digitalis induced arrhythmias
Note- little effect on supraventricular arrhythmias, and amiodarone is superior drug of choice
list the adverse effects of lidocaine
(wide therapeutic window)
- CNS: drowsiness, slurred speech, agitation, etc
- Toxic doses: convulsions, coma
-cardiac arrhythmias (10%), little impairment of LV, NO neg. inotropic effects
(1) is the orally active derivative of lidocaine. It mainly is used to treat (2). Its adverse effects include (3).
1- mexiletine (although administered orally, IV)
2- severe ventricular arrhythmias
3- CNS and GI effects
The main class I-C antiarrhythmic drugs are (1). The will bind and dissociate from (2) channels slowly, and affect the (3) phase of myocardial action potentials. They are used cautiously due to (4) property.
1- flecainide, propafenone 2- Na channels 3- phase 0, prolonged QTS (although no effect on QT / phase 3 b/c no K channel effect like class I-A/B) 4- pro-arrhythmic
the most potent class I antiarrhythmic drugs are….
class I-C: flecainide, propafenone
they only block Na channels, no effect on K channels like class I-A (strong) and I-B (weak)
Flecainaide is a class (1- indicate MOA) antiarrhythmic drug. It is used to treat (2) and (3).
1- class I-C, Na channel blocker
2- severe symptomatic ventricular arrhythmias: premature ventricular contraction or ventricular tachycardia (resistant to other therapies)
3- severe symptomatic supraventricular arrhythmias and prevention of paroxysmal AFib
list the adverse effects of Flecainide
**life-threatening arrhythmias and ventricular tachycardia (worse in people with structural heart disease)
- Neg. ionotropic: aggravated CHF
- CNS: dizziness, blurred vision, HA
- GI: n/v/d
Propafenone is a class (1- indicate MOA) antiarrhythmic drug. It is used to treat (2) and (3).
1- class I-C, Na channel blocker 2- life-threatening ventricular arrhythmias 3- maintenance of normal sinus rhythm in symptomatic AFib patients
list the adverse effects of Propafenone
**life-threatening arrhythmias and ventricular tachycardia (worse in people with structural heart disease)
- Neg. ionotropic: aggravated CHF
- CNS: dizziness, blurred vision, HA
- GI: n/v/d
Unlike Flecainide- its has β-blocker activity => bronchospasm –> aggravating underlying HF
Class II antiarrhythmic drugs are (1) type drugs. There main effect is to affect (2), therefore it effects (3) part of the heart. This will in turn also cause (4) in the heart, leading to (5).
1- β-blockers
2- reduce HR, contractility via β1
3- AV node, little effect on myocardial AP
4- reduce rate of spontaneous depolarization in pacemaker cells
5- slow conduction of impulses thru myocardial conducting system
The main class II anti-arrhythmic drugs are (1). They are used in the following situations: (2), (3), (4). (5) is used in treatment of acute arrhythmias because of its (6) properties.
1- metoprolol (β1), propanolol (β1/2)
2- reduce incidence of sudden arrhythmic death post-MI
3- control suprventricular tachycardias (AFib/flutter, AV nodal re-entrant tachycardia)
4- ventricular tachycardia (catecholamine induced, digoxin toxicity)
5- esmolol (β1)
6- short-acting, short half life- 9 mins
list the general adverse effects and contraindications of class II antiarrhthymic drugs
(β-blockers)
-bradycardia, HTN, CNS effects
Contraindications: severe bradycardia, heart block, sever hyperactive airway disease
The main class III antiarrhthymic drug is (1) which functions to block (2) and therefore affect phase (3). The main risk of class III drugs are (4).
1- amiodarone
2- K channel blockers
3- phase 3, prolongs repolarization / QT segment (effective refractory period)
4- pro-arrhythmic
Amiodarone is a class (1- include MOA) anti-arrhythmic drug. It importantly contains (2) in its structure. Its MOA will function to decrease (3).
1- class III, K channel blocker (+ class I, II, and some IV effects) 2- iodine, similar to thyroxine structure (reason for several adverse effects) 3- dec AV conduction, SA function
Amiodarone has (wide/limited) uses. It is mainly used in the management of (2) and is the drug of choice for (3). It can also be used in low doses for (4).
(class III, K channel blocker)
1- widely used
2- ventricular and supraventricular arrhythmias
3- acute ventricular tachycardia (refractory to cardioversion shock)
4- AFib, to maintain normal sinus rhythm
describe the pharmacokinetics of amiodarone
- oral and IV (acute)
- half-life is several weeks + large Vd => large loading dose required
- full clinical and adverse effects may take 6 weeks to achieve
the main adverse effect of amiodarone is (1), the most visible effect will (2), and the other effects include (3)
1- pulmonary fibrosis
2- blue skin discoloration (via iodine accumulation, harmless effect)
3- GI intolerance, tremor, ataxia, dizziness, hyper/hypo-thyroidism, liver toxicity, photosensitivity, neuropathy, muscle weakness, hypotension, bradycardia, AV block, arrhythmias
list the contraindications for amiodarone
Drugs (patients taking): digoxin, theophylline, warfarin, quinidine
- bradycardia
- SA/AV block
- severe hypotension
- severe respiratory failure**
Sotalol is a class (1) anti-arrhythmic drug with a (2) MOA which functions to have (3) as its end goal.
1- class III 2- K channel blocker, potent non-selective β-blocker 3- prolongs repolarization / inc AP duration / lengthens refractory period (Phase III of myocardial AP)
Sotalol is used to treat the following…..
(class III- K channel blocker, potent non-selective β-blocker)
- life-threatening ventricular arrhythmias
- maintain sinus rhythm in AFib/flutter patients
**do not use in asymptomatic arrhythmias since it is a pro-arrhythmic
sotalol adverse effects
- same as β-blockers
- pretty low rate of adverse effects
- torsades de pointes (prolongs QT interval)
- use in caution with renally impaired patients
Dofetilide is a class (1- include MOA) antiarrhythmic drug. It is used for (2) and (3). Its adverse effects include (4).
1- class III, K channel blocker (potent and pure- no other actions) 2- converts AFib to normal sinus rhythm 3- maintain normal sinus rhythm in AFib 4- HA, chest pain, dizziness, ventricular tachycardia, torsade de pointes (prolonged QT)
Class IV antiarrhythmic drugs effect (1) in order to change (2) phase of the nodal action potential.
1- Ca channel blocker
2- delays phase 0, prolongs start of depolarization (guess delays phase 4??)
(SA, AV nodes)
The main class IV drugs used are (1) and (2), include differences in target selectivity. They have the following major effects: (3).
1- verapamil: more selective for myocardium than vasculature
2- diltiazem: intermediate selectivity for myocardium between verapamil and dihydrooyridines
3: (* indicates the goal of the drug)
- neg. inotropic, dec contractility
- *neg. chronotropy, dec HR
- *neg. dromotropy, dec conduction velocity
Class IV drugs are mainly used for…..
(better for atrial than ventricular arrhythmias)
-supraventricular tachycardia => reduces ventricular rate in AFib
-HTN, angina
describe the MOA of digoxin in terms of arrhythmias (include clinical application)
- shortens refractory period in atrial and ventricular *myocardial cells (pos. inotropy)
- prolong effective refractory period + diminishes conduction velocity in *AV node (inc vagal stimulation –> inc PR interval)
-used to control ventricular response rate in AFib/flutter w/ impaired LV function or in HF (pos. inotropy)
what are the major indirect actions of digoxin
- hyperpolarization
- shortens atrial action potentials
- inc AV node refractoriness
the main adverse effect of toxic doses of digoxin is (1) leading to (2); (3) is administered to reverse these effects
1- ectopic ventricular beats
2- ventricular tachycardia
3- lidocaine (class I-B, Na channel blocker)
Adenosine acts on (1) receptors on (2) cells in order to decrease (3) and increase (4) at high doses for arrhythmias
1- P1 receptor (agonist)
2- AV node
3- dec conduction velocity
4- prolongs refractory period (dec automaticity of AV node)
Note- half-life 15s, IV infusion
Adenosine acts on (1) receptors on (2) cells in order to influence (3) conduction which will affect (4) levels in the cell leading to (5).
1- P1 receptor (agonist) 2- AV node 3- enhance K conductance 4- inhibit cAMP mediated Ca influx 5- hyperpolarization in AV node (dec chance of action potential)
(1) is the drug of choice in abolishing acute supraventricular tachycardia
(2) is for ventricular tachycardia
1- adenosine
2- amiodarone (K channel blocker)
list the adverse effects of adenosine
(low toxicity)
- flushing
- burning
- chest pain
- hypotension
- **bronchoconstriction in asthmatics up to 30 mins
(1) is a functional antagonist of Ca. It is used in the treatment of the following: (2).
1- Mg2+
2:
- torsades de pointes (prolonged QT)
- digitalis (digoxin) induced arrhythmia
- prophalaxis of arrhythmia in acute MI
what is the use of atropine is terms of arrhythmias
-bradyarrhythmia to dec vagal tone
Drugs used to target SA node in arrhythmias….
- β-blockers (II)
- Ca channel blockers (IV)
- digoxin
Drugs used to target AV node in arrhythmias….
- Ca channel blockers (IV)
- β-blockers (II)
- digoxin
Drugs used to target Atrial myocytes in arrhythmias….
- Class I-A, I-C (Na channel blockers)
- K channel blockers (III)
Drugs used to target Ventricular myocytes in arrhythmias….
- Na channel blockers (I)
- K channel blockers (III)
Drugs used to target accessory pathways in arrhythmias….
- Class I-A (Na channel blockers + K channel blocker)
- K channel blockers (III)
list the drugs that can treat both ventricular and supraventricular arrhythmias
- Class I-A/C (Na channel blockers)
- K channel blockers (III)
list the drugs that treat mainly ventricular arrhythmias
-Class I-B: lidocaine, mexiletine (Na channel blockers that are also weak K channel blockers)
list the drugs that treat mainly supraventricular arrhythmias
- Ca channel blockers (IV)
- β-blockers (II)
AFib drugs involved in rate control
w/o HF: Ca channel blockers (IV), β-blockers (II)
w/ HF: digoxin
(when others can’t be used): amiodarone (III)
**neg. dromotropic agents - slow ventricular rate
AFib drugs involved in rhythm control
- class I-C (Na channel blockers): flecainide, propafenone
- class III (K channel blockers): amiodarone, dofetilide
**induction / maintenance of sinus rhythm
in addition to traditional or direct acting drugs for AFib, it is important to also administer (1) for (2) to avoid (3)
1- heparin (IV), warfarin (oral)
2- thrombus degradation or prevention
3- stroke, MI
