Antiarrhythmics Flashcards
what channels/receptors do class III agents effect
K+, Ca2+, Na+ channels & autonomic receptors
main effect of class III agents
prolong phase 3 repolarization; increase QT
Effective in many types of arrhythmias
what are the class III agents
Amiodarone
Ibutilide
Dofetelide
Dronedarone
Sotalol
(AIDDS)
class III
Blocks K+ channels –> prolongs refractoriness and APD
Blocks Na+ channels that are in the inactivated state
Block Ca2+ channels –> slows SA node phase 4
Slows conduction through the AV node
Noncompetitive blockade of α-, β-, and M receptors
Explains diverse antiarrhythmic actions
Amiodarone
clinical applications of amiodarone
Conversion and slowing of Af, maintaining sinus rhythm in Af (rx of choice)
AV nodal reentrant tachycardia
IV for acute termination of VT or VF and is replacing lidocaineas first-line therapy for out-of-hospital cardiac arrest
explain pharmacology of amiodarone
highly lipophilic
metabolize to DEA: DEA has antiarrythmic potency >/= amiodarone
what may be responsible for early recurrence of arrhythmias after discontinuation or rapid dose reduction of amiodarone
Until all tissues are saturated, rapid redistribution out of the myocardium
most serious adverse rxn to amiodarone
other SE
most serious: lethal pulmonary fibrosis
Hyperthyroidism or hypothyroidism
elevated serum hepatic enzyme levels
what should be checked when someone is taking amiodarone
Check PFTs (CXR/3 months), LFTs, & TFTs when using amiodarone
MOA of Ibutilide
Blocks the rapid component of the delayed rectifier K+ current –> slows cardiac repolarization.
Activation of slow inward Na+ current --> prolong AP. (other class III are not acting on Na+)
therapeutic use of ibutlide
IV: acute conversion of atrial flutter and atrial fibrillation to NSR (20 min
SE of ibutilide
Excessive QT-interval prolongation and Torsades de Pointes.
MOA of dofetilide
Dose-dependent blockade of delayed rectifier K+ current (IKr) (blockade IKrincreases in hypokalemia)
Does not block other K+ channels.
clinical use of dofetilide
Restore & maintenance of normal sinus rhythm in patients with Afib.
SE of dofetilide
Dose-dependent QT interval prolongation and ventricular proarrhythmia
MOA of sotalol
Has both β-blocking & AP-prolonging actions.
acting on K+ channe
clinical use of sotalol
Life-threatening ventricular arrhythmias
SE of sotalol
Dose-related torsades de pointes
class IV agents
Verapamil
Diltiazem
what channels do class IV agents blcok
Ca2+
action of class IV agents
depressed SA nodal automaticity,
AV nodal conduction,
decreased ventricular contractility
what interval is increased by class IV
PR interval
which Ca2+ subunit contains pores
alpha1
Ca2+ channel blockers (CCBs) interfere with the entry of Ca2+into cells through voltage-dependent _____ channels.
L- and T-type Ca2+
where are CCB major cardiovascular sites of action
vascular smooth muscle cells
cardiac myocytes
SA and AV nodal cells
By binding to specific sites in Ca2+ channel subunits,CCBs diminish the degree to which the Ca2+ channel pores _____
open in response to voltage depolarization
which CCBs mainly effect the vasculature
Dihydropyridine (DHP): Nifedipine
which CCBs mainly effect the heart?
Non-dihydropyridine (NDHP)
Phenylalkylamine - Verapamil
Benzothiazepine - Diltiazem
–used as antiarrhythmics
for CCBs where is vasodilation more seen
more marked in arterial and arteriolar vessels than on veins
which CBCs have Negative chronotropic and dromotropic effectsare seen on the SA and AV nodal conducting tissue
NDHP agents only (verapamil, diltiazem)`
ratio of vasodilation to negative inotropy for the protoype CCBs?
10 : 1 for nifedipine,
1 : 1 for diltiazem and verapamil.
do CCBs have effect on non-cardiovascular smooth muscles
will skeletal muscles respond to CCBs?
no
no
non-cardiovascular effect of CCBs
CCBs may relax uterine smooth muscle and have been used in therapy for preterm contractions
what CCBs have IV formulations available
Verapamil, Diltiazem, Nicardipine, Clevidipine (only IV)
MOA of verapamil
↓SA automaticity ↓HR
↓AV conduction velocity –> ↑PR interval
Increased ERP
Cardiac depression (decrease ventricular contractility and HR)
No effect on ventricular Na+ conduction –> ineffective on ventricular arrhythmia
clinical application of verpamil
Prevention (PO) or conversion (IV) of nodal arrhythmias: PSVT
Rate control in Afib
SE of verapamil
Constipation
Exacerbate CHF
contraindications of verapmil
WPW syndrome with Afib
Ventricular tachycardia
MOA of adenosine
Activates A1receptors in SA & AV nodes –> open K+ channels –> increase K+ efflux –>
- SA node hyperpolarization and decrease firing rate
- Shortening of AP duration of atrial cells
- Depression of A-V conduction velocity
Activates A2receptor in vasculature –> K+ channels
- increase endothelial Ca2+ –> increase NO
- Smooth muscle hyperpolarization –> vasodilation
- stimulates pulmonary stretch receptors
clinical use of adenosine
Very effective for acute conversion of paroxysmal supraventricular tachycardia caused by reentry involving accessory bypass pathways.
Adenosine pharmacology:
how is adenosine administered?
what blunts adenosines effects?
t½=10-15 sec
Must use as IV bolus to a central vein (brachial, antecubital)
Effects blunted by adenosine receptor antagonists: theophylline & caffeine
clinical use of magnesium
Torsades de pointes
Digitalis-induced arrhythmias
what can be used to tx bradycardia
atropine (vagal block increases HR)
isoproterenol (B1 stim.)
pacemaker
what can be used to tx sinus tachycardia, PSVT
vagal stimulation through carotid sinus massage or Valsalva maneuver
what are the 4 ways of decreasing spontaneous activity
decrease phase 4 slope
increased threshold
increased maximum diastolic potential
increased action potential duration
what are two ways to increase refractoriness
Na+ channel blockade
- shifts voltage dependence of recovery and so delays the point at which sufficient Na+ channels have recovered prolonging refractoriness
Drugs that prolong AP will also extend ERP point without interacting with Na+ channels
Na+ channel blockers bind and block the channels when they are in the 1 and 2 states, but not in the 3 state.
- open
- inactivated
- resting
State-dependent blockade - consequences:
Slower 1 rates
increases Na+ channel block
2 increases Na+ channel block
- drug dissociation
2. Tachycardia
what are class I agents useful for?
***MI induced arrhythmia
- ventricular dysrhythmia
- digitalis
MOA for class I agents
- *Block fast inward Na+ channels to varying degrees in conductive tissues of the heart**
- Decrease maximum depolarization rate (Vmax of phase 0)
- reduce automaticity, delay conduction
- Prolong ERP –> ERP/APD increased
how can class I agents tx re-entry
block Na+ channels - decrease excitability
block K+ channels - increase ERP
what do class Ia agents include
Quinidine, Procainamide, Disopyramide
The Queen Proclaims Disos Pyramid
Class Ia agents
‘Moderate’ binding to 1 channels
- moderate effects on phase 0 depolarization
2 channel blockade
- delayed phase 3 repolarization
- prolonged QRS and 3
- Na+
- K+
- QT
primary MOA of quinidine (class Ia)
Primary: Block rapid inward Na+ channel:
- Decreased Vmax of phase 0
- Slowed conduction (His-Purkinje > atria)
- Effects greatest at fast HR (state-dependent block)
aside from quinidines primary MOA of blocking rapid inward Na+ channels, what else do they do?
- multiple actions - dose dependent effect
Block K+ channels - increase APD
Block α receptors - decrease BP
Block M receptors - increase HR in intact subjects
clinical application of quinidine
Now mainly used in refractory patients to:
- Convert symptomatic AF or flutter
- Prevent recurrences of AF
- Treat documented, life-threatening ventricular arrhythmias
SE of quinidine
Diarrhea (most common)
cinchonism (headache, tinnitus, hearing loss, blurred vision)
hypotension due to α-adrenergic blocking effect
proarrhythmic (torsades de pointes – increased QT interval)
MOA of procainamide (class Ia)
Block rapid inward Na+ channel –> slows
conduction
automaticity
excitability
Blocks K+ channels –> prolongs APD & refractoriness
which class I agent has very little vagolytic activity and does not prolong the QT interval to as great an extent
procainamide
what does procainamide treat
Ventricular:
treat documented, life-threatening ventricular arrhythmias
Supraventricular: acute tx of:
- Reentrant SVT
- Atrial fibrillation
- Atrial flutter associated with Wolff-Parkinson-White syndrome
SE of procainamide
Cardiac:
- arrhythmia aggravation
- torsades de pointes
Extracardiac:
- SLE-like syndrome
- GI nausea and vomiting
when is procainamide contraindicated
(contraindicated in long QT syndrome,
history of TdP,
hypokalemia)
what are the class Ib agents
Lidocaine, Mexiletine
First Aid’s mnemonic: I’d Buy Liddy’s Mexican Taco
MOA of class Ib
‘Weak’ binding to Na+ channels
- weak effect on phase 0
Accelerated phase 3 repolarization
- shortened APD and QT interval
what are class Ib agents good to use for
digitalis and MI-induced arrhythmia
MOA of lidocaine
Blocks inactivated»_space; open Na+ channels - reduces Vmax
Shorten cardiac action potential
Lowers the slope of phase 4; altering threshold for excitability
produces variable effects in abnormal conduction system
- Slows ventricular rate
- Potentiates infranodal block
Lidocain is more effective in what tissues?
ischemic
how is lidocaine more effective in ischemic tissues
Ischemia causes:
- Prolonged depolarization
- Slow-inactivated state of Na+ channel
- depolarized resting potential (-60 mv)
1) Lidocaine (Ib) blocks I»_space; O –> blocks slow-inactivated Na+ channels that are important in ischemic tissue –> shortens AP
2) Slower dissociation rate –> increase rx effect
clinical applications for lidocaine
post-MI (best)
how should lidocaine be administered
Extensive first-pass hepatic metabolism –> IV use.
need multiple loading doses and a maintenance infusion
SE of lidocaine
rapid bolus: tinnitus, seizure
what the class Ic agents?
Propafenone, Flecainide
MOA of class Ic agents (Propafenone, Flecainide)
- **Strongest binding to Na+ channels (O state)
a) slow dissociation – strong effects on phase 0 depolarization
b) *lengthened QRS, less on APD
c) Little effect on repolarization - QT unchanged
d) lengthened PR (depressed AV nodal conduction)
MOA of propafenone
**Strong inhibitor of Na+ channel
Can inhibits beta-adrenergic R: marked structural similarity to propranolol
Clinical application of propafenone
ventricular arrhythmias in patients with no or minimal heart disease and preserved ventricular function
MOA of flecainide
potent Na+ channel blockade –> prolongs phase 0 and widens QRS
***markedly slows intraventricular conduction
clinical application for Flecainide
use only in the treatment of refractory life-threatening ectopic ventricular arrhythmia
**not considered a first-line agent due to propensity for fatal proarrhythmic effects
Class Ic SE
Proarrhythmic, especially post-MI
what are class Ic agents contraindicated in?
structural and ischemic heart disease
what are the class II agents
Beta adrenergic antagonists
Metoprolol, Propranolol, Esmolol, Atenolol, Timolol, Carvedilol
MOA of class II agents (Metoprolol, Propranolol, Esmolol, Atenolol, Timolol, Carvedilol)
decrease cAMP, decrease Ca2+ currents –>
- decrease SA nodal automaticity (phase 4);
- decrease AV nodal conduction
- decrease Ventricular contractility
what are class II agents effective for?
supraventricular arrhythmias due to excessive sympathetic activity
Are the only antiarrhythmic drugs found to be clearly effective in preventing sudden cardiac death in patients with prior MI
class II agents - beta adrenergic antagonists
Metoprolol, Propranolol, Esmolol, Atenolol, Timolol, Carvedilol
what class II agent has a very short half life and is only used IV
- useful when short termed beta blockade is desired (aortic dissection, critically ill pts, postop HTN)
esmolol
SE of class II agents
- Impotence
- Exacerbation of COPD & asthma
- Bradycardia, AV block, heart failure; mask signs of hypoglycemia
- CNS: sedation, sleep alterations
- Dyslipidemia: Metoprolol
- Exacerbation of Prinzmetal angina: Propranolol
- Unopposed alpha1 agonism if given alone in pheochromocytoma or cocaine toxicity, except carvedilol & labetalol (blocking both alpha and beta)
main clinical applications of CCBs - both dihydropyridines and nondihydropyridines
systemic HTN
angina pectoris
coronary spasm
Main clinical applications of CCBs for only nondihydropyridines
SVT
Post-infarct
