CV-antiarythmics Flashcards
Class Ia antiarrhythmic agents:
QUINIDINE, PROCAINAMIDE, DISOPYRAMIDE
Class Ia antiarrhythmic agents:
‘Moderate’ binding to Na+ channels
moderate effects on phase 0 depolarization
K+ channel blockade
delayed phase 3 repolarization
prolonged QRS and QT
Ca2+ channel blocking effect at high doses
depressed phase 2 and nodal phase 0
‘Moderate’ binding to Na+ channels
moderate effects on phase 0 depolarization
K+ channel blockade
delayed phase 3 repolarization
prolonged QRS and QT
Ca2+ channel blocking effect at high doses
depressed phase 2 and nodal phase 0
Class I general characteristics
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
useful in varying degrees for ventricular dysrhythmia and/or digitalis or MI-induced arrhythmia
Quinidine MOA
Primary: Block rapid inward Na+ channel
Decreased Vmax of phase 0
Slowed conduction (His-Purkinje > atria)
Effects greatest at fast HR
Multiple actions – dose-dependent effects
Block K+ channels - APD
Block α receptors - BP
Block M receptors - HR in intact subjects
Clinical use quinidine
Risk/benefit ratio must be considered in each patient
Only used in refractory patients to
Convert symptomatic AF or flutter
Prevent recurrences of AF
Treat documented, life-threatening ventricular arrhythmias
Quinidine adverse effects
nausea, vomiting, diarrhea (most common)
cinchonism (tinnitus, hearing loss, blurred vision)
hypotension due to α-adrenergic blocking effect
proarrhythmic (torsades de pointes – increased QT interval)
MOA procainamide
Block rapid inward Na+ channel slows
conduction
automaticity
excitability
Blocks K+ channels prolongs APD & refractoriness
Diff tween Quinidine and Procainamide
Cf. Quinidine: Procainamide has very little vagolytic activity and does not prolong the QT interval to as great an extent, less likely to cause torsades de pointes
Ventricular Clinical use Procainamide*
life-threatening ventricular arrhythmias occurig post MI
Supra ventricular clinical use of Priocainamide*
Reentrant SVT
Atrial fibrillation
Atrial flutter associated with Wolff-Parkinson-White syndrome
Adverse effects Procainamide
40% stop use in 6 months
Cardiac:
arrhythmia aggravation, torsades de pointes (contraindicated in long QT syndrome, history of TdP, hypokalemia)**
heart block, sinus node dysfunction
Extracardiac:
*SLE-like syndrome: (15-20%, in slow acetylators) arthralgia, pericarditis, fever, weakness, skin lesions, lymphadenopathy, anemia and hepatomegaly
*GI nausea and vomiting: very common
Decrease kidney functions
Class Ib agents
Lidocaine, Phenytoin, Mexiletine, Tocainide
Class Ib general characterisitcs
‘Weak’ binding to Na+ channels
weak effect on phase 0 depolarization due to rapid ‘on-off’ receptor kinetics
Accelerated phase 3 repolarization
shortened APD and QT
clinical use for Ib agents*
digitalis and MI-induced arrhythmia
MOA Lidocaine
Blocks open and inactivated Na+ channels - reduces Vmax**
Shorten cardiac action potential
More effective in ischemic tissues
Lowers the slope of phase 4; altering threshold for excitability
produces variable effects in abnormal conduction system
Slows ventricular rate
Potentiates infranodal block
Clinical use Lidocaine
Used to be first-line rx for ventricular arrhythmias (post-MI)
Now (ECC/AHA 2005): second choice behind amiodarone for
immediately life-threatening or symptomatic arrhythmias
Ineffective for prophylaxis of arrhythmias after MI
Ineffective in atrial tissue
Pharmokinetics of interest
Extensive first-pass hepatic metabolism sobetter IV use.
need multiple loading doses and a maintenance infusion
Adverse effects lidcaine
rapid bolus: tinnitus, seizure
High doses: drowsiness, confusion, hallucinations, coma
Cardiac functions dec so dec clearance, inc concentrations
Class Ic agents
Moricizine, Flecainide, Propafenone
Class Ic general characteristics
Strongest binding to Na+ channels*
slow ‘on-off’ kinetics – strong effects on phase 0 depolarization
lengthened QRS and APD
Little effect on repolarization - QT unchanged
lengthened PR (depressed AV nodal conduction)
Propafenone MOA
Strong inhibitor of Na+ channel*
Can inhibits B-adrenergic R: marked structural similarity to propranolol
Propafenone Clinical use
used primarily to treat atrial arrhythmias, PSVT, and ventricular arrhythmias in patients with no or minimal heart disease and preserved ventricular function
Flecainide MOA
potent Na+ channel blockade prolongs phase 0 and widens QRS
markedly slows intraventricular conduction
Flecainide clinical usage
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 II general characterisitics
B-adrenergic antagonists
Decrease: SA nodal automaticity (phase 4)
AV nodal conduction
Ventricular contractility
Effective for supraventricular arrhythmias due to excessive sympathetic activity
Not very effective in severe arrhythmias such as recurrent VT
Are the only antiarrhythmic drugs found to be clearly effective in preventing sudden cardiac death in patients with prior MI
Class II- B adreneergic antagonists general use etc
Multiple effects at K+, Ca2+, Na+ channels & β-receptors
Main effect: prolong phase 3 repolarization; inc QT
Useful for ventricular re-entry/fibrillatory arrhythmia
Effective in many types of arrhythmias
Class II B adrenergic antagonists
Dronedarone, Amiodarone, Sotalol, Ibutilide, Dofetilide - DASID
Amiodarone MOA
diverse pharmacologic actions
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 usage
Effective in a wide range of arrhythmias, now very widely used**
Conversion and slowing of AF, maintaining sinus rhythm in AF
AV nodal reentrant tachycardia
Tachycardias associated with the WPW syndrome
PO for recurrent life-threatening VT or VF resistant to other rx
IV for acute termination of VT or VF and is replacing lidocaineas first-line therapy for out-of-hospital cardiac arrest**
pharmokinetics Amiodarone
highly lipid-soluble compound
extremely variable and complex pharmacokinetics
extensively metabolized to desethyl amiodarone (DEA)
DEA has antiarrhythmic potency greater than amiodarone*
rapidly concentrated in some tissues, including myocardium, but it accumulates more slowly in others very large VD
Until all tissues are saturated, rapid redistribution out of the myocardium may be responsible for early recurrence of arrhythmias after discontinuation or rapid dose reduction**
After IV administration: T1/2 5 – 68 hrs
As tissues become saturated: T1/2 13 to 103 days
Adverse effects Amiodarone
IV > 5mg/kg decreases cardiac contractility & PVR hypotension***
Usual dosages improve myocardial contractility
- Most serious: lethal interstitial pneumonitis, more frequent in patients with preexisting lung disease. Reversible with CXR/3 months
- Hyperthyroidism or hypothyroidism: diverse effects on the thyroid
Accumulation of corneal microdeposits
Photosensitivity
Elevated serum hepatic enzyme levels
Class IV agents
Verapamil, Diltiazem
Class IV general characterisitcs
Ca2+ channel antagonists (cardiac)
similar in utility to Class II agents with primary effects on nodal phase 0 depolarization
depressed SA nodal automaticity, AV nodal conduction, decreased ventricular contractility
Calcium blockers (class 4) major cardiovascular sites of action
vascular smooth muscle cells
cardiac myocytes
SA and AV nodal cells
Calcium channel blocker characterisitcs and which 2 subtype of calcium channels are affected?
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
Ca2+ channel blockers (CCBs) interfere with the entry of Ca2+into cells through voltage-dependent L- and T-type Ca2+ channels.**
L-type Ca2+ channel 1 subunit
- No CCB binds to all pores blockade is incomplete
4 subunits a-1, a-2, B, y
a-1 containspores
CCB 2 classes
DHP (Dihydropyridine) and NDHP (Nondihydopyridine)
Dihydropyridine (DHP) (1)
Nifedipine
Effects mainly in the vasculature
NDHP
Phenylalkylamine - Verapamil & derivatives
Benzothiazepine - Diltiazem & derivatives
*both affect mainly in heart
Cardiovascular effects CCB
Vasodilation
more marked in arterial and arteriolar vessels than on veins
Negative inotropic effectsare seen on myocardial cells; in the case of DHPs, this effect may be offset by reflex adrenergic stimulation after peripheral vasodilation.
Ratios of vasodilation to negative inotropy for the prototype CCBs were 10 : 1 for nifedipine, 1 : 1 for diltiazem and verapamil.
Cardiovascular events occuring only with NDHP
Negative chronotropic and dromotropic effectsare seen on the SA and AV nodal conducting tissue (NDHP agents only).
CCB non cardiovascular effects (or lack there of)
CCBs have little or no effect on other smooth muscle
CCBs may relax uterine smooth muscle and have been used in therapy for preterm contractions
Skeletal muscle does not respond to conventional CCBs
Main clinicaluses of CCB
Systemic Hypertension
Angina Pectoris
Supraventricular Tachycardia
Post-infarct protection
Veramapil MOA
“slow” inward Ca2+ channels in nodal tissue are primarily affected ↓SA automaticity ↓HR ↓AV conduction ↑PR interval cardiac depression (↓ ventricular contractility and ↓HR) no effect on ventricular Na+ conduction ineffective on ventricular arrhythmia
Veramapil clinical applications
supraventricular tachycardia (IV – conversion, PO – maintenance)
rate control in Afib
angina pectoris
hypertension
Veramapil adverse effects
Headache, flushing, dizziness, ankle edema
Constipation
Exacerbate CHF
Hypotension (IV)
AV heart block in combination with β-blockers
Contraindications
Sick sinus syndrome
Pre-existing AV nodal disease
WPW syndrome with Afib
Ventricular tachycardia
Misc. antiarrythmia drugs
Adenosine, Digoxin
Adenosine MOA A1 rec
Activates A1receptor in SA & AV nodes activates cAMP–independent, Ach/Ado-sensitive K+ channels
SA node hyperpolarization and dec firing rate
Shortening of AP duration of atrial cells
Depression of A-V conduction velocity
Adenosine MOA A2 rec
Activates A2receptor in vasculature K+ channels
inc endothelial Ca2+ - inc
NO
Smooth muscle hyperpolarization - vasodilation
Stimulates pulmonary stretch receptors
Clin use adenosine
Very effective for acute conversion of paroxysmal supraventricular tachycardia caused by reentry involving accessory bypass pathways. At a dose of 6mg, 60% of patients respond, and an additional 32% respond when given a 12-mg dose.
Pharmokinetics Adenosine
susceptibility to degradation and rapid plasma metabolism
Must use as IV bolus to a central vein (brachial, antecubital)
t½=10-15 sec
enzymatic metabolism in erythrocytes and vascular endothelium
Adenosine adverse effects
hypotension, flushing, complete heart block, CNS effects, dyspnea
Management of Bradycardia
atropine – produces a vagal block to increase HR
isoproterenol – β1-stimulated increase in HR
Pacemaker
Management of Sinus tachcardia or PSVT
vagal stimulation through carotid sinus massage or Valsalva maneuver
