Exam 2 Week 1- Anti-arrhythmic Agents Flashcards
Phase 0 (Cardiac Cell)
rapid depolarization (fast sodium channels open; fast inward flow of Na+)
Phase 1 (Cardiac Cell)
beginning of repolarization (sodium channels close)
Phase 2 (Cardiac Cell)
plateau (slow calcium channels open; slow inflow of Ca2+)
Phase 3 (Cardiac Cell)
repolarization (calcium channels close; potassium channels open; slow outward K current)
Phase 4 (Cardiac Cell)
pacemaker potential; returning to resting membrane potentials
Refractory period (Cardiac Cell)
phases 1-3
periods of repolarization
Phase 0 (SA/AV Node)
upstroke
critical firing threshold (-40mV)
slower and Ca2+ mediated
Phase 3 (SA/AV Node)
repolarization
inactivation of Ca2+ and Na+ channels
activation of K channels
Phase 4 (SA/AV Node)
gradual depolarization
slow inward Na and Ca2 currents
What node is the cardiac pacemaker?
Sino-atrial
Normal sinus rhythm is
60-100bpm
Which node conducts more slowly then the SA?
AV node
Which node conducts faster then the AV node?
Purkinje fibers
P wave indicates
Atrial depolarization
QRS complex represents
ventricular depolarization
T wave represents
ventricular repolarization
What is an arrhythmia
is the disturbance in the electrical activity of the heart
Classification of arrhythmia
site of origin of abnormality (atrial/junctional/ventricular)
complexes on ECG
Heart Rhythm (regular/irregular)
Heart rate is increased or decreased
Mechanisms of arrhythmia production
Altered automaticity
delayed after-depolarization
re-entry
conduction block
Altered automaticity
latent pacemarker cells take over the SA node’s role; escape beats
Delayed after-depolarization
normal action potential of cardiac cell triggers
Re-entry
refractory tissue reactivated repeatedly and rapidly due to unidirectional block, which causes abnormal continuous circuit
Conduction Block
impulse fail to propagate in non-conducting tissue
Supraventricular Drugs
adenosine IV
digoxin
verapamil
Stress Induced Drugs
Class 2
beta blockers, propanolol, atenolol, sotalol
Sinus Bradycardia drugs
atropine IV
Ventricular and supra-ventricular drugs
Class 3- amiodarone, sotalol
Class 1A- procainamide and disopyramide
Class 1C- flecanide, propafenone
Ventricular Drugs
class 1B- lidocaine, mexlietine
Factors underlying cardiac arrhythmias
arterial hypoxemia electrolyte imbalance acid-base abnormalities myocardial ischemia altered sympathetic nervous system activity bradycardia administration of certain drugs enlargement of a failing ventricle
When do cardiac arrhythmias require treatment?
they cannot be corrected by the removing the precipitating cause
hemodynamic stability is compromised
the disturbance predisposed to more serious cardiac arrhythmias or co-morbidities
Non-pharmacological treatment
acute: vagal manuevers/cardioversion
Prophylaxis: radiofrequency catheter ablation/ implantable defibrillator
Pacing: External, temporary, permanent
What anti-arrhythmic agents utilized for?
used to prevent, suppress or treat a disturbance in cardiac rhythm
Class 1 Anti-arrhythmic Drug Class
Sodium Channel Blockers/Phase 0
Class 2 Anti-arrhythmic Drug Class
Beta adrenergic blocker/ Phase 4
Class 3: Anti-arrhythmic Drug Class
Potassium Channel Blockers
Class 4: Anti-arrhythmic Drug Class
Calcium Channel blockers
Class 5: Anti-arrhythmic Drug Class
Unclassified drugs
Electrophysiologic Effect of Class 1 Anti-Arrhythmic Drugs
depression of phase 0 depolarization (block of sodium channels)
Results in decreases in action potential propogation (decrease in depolarization rate) and slowing conduction velocity
membrane stabilizing agents
Binds to open or inactive gate best, not resting state
Electrophysiologic Effect of Class 1A Anti-Arrhythmic Drugs
Moderate depression and prolonged repolarization
Electrophysiologic Effect of Class 1B Anti-Arrhythmic Drugs
weak depression and shortened repolarization
Electrophysiologic Effect of Class 1C Anti-Arrhythmic Drugs
strong depression with little effect on repolarization
Electrophysiologic Effect of Class 2 Anti-Arrhythmic Drugs
Beta adrengeric blocking effects
Electrophysiologic Effect of Class 3 Anti-Arrhythmic Drugs
prolongs repolarization (blocks potassium channels)
Electrophysiologic Effect of Class 4 Anti-Arrhythmic Drugs
Calcium channel-blocking effects
Other Anti-arrhythmic Drugs
Adenosine, adenosine triphosphate, digoxin, and atropine
Class 1A Drugs
quindine, procainamide, disopyramide
Class 1B Drugs
lidocaine, mexiletine, phenytoin, tocainide
Class 1C drugs
flecainide, propafenone, moricizine
Class 2 drugs
esmolol, propanolol, metoproplol, timolol, pindolol, atenolol, acebutuolol, nadolol, carvedilol
Class 3 drugs
amiodarone, bretylium, sotalol, ibutilide, dafetilide
Class 4 Drugs
verampil, dilitiazem
Class 1 Agents treat
SVT, AF, WPW
Class 1A Agents
slow conduction velocity and pacemaker rate
intermediate sodium channel blocker (immediate dissociation)
direct depressant effects on SA and AV node (decrease automaticity)
Decreased depolarization rate (phase 0)
prolonged repolarization
Increased AP duration
Used for atrial and ventricular arrhythmias
Eliminated by hepatic metabolism
Implication in reversible lupus like syndrome
increases QT duration
Disopyramide
suppresses atrial and ventricular tachyarrhythmias
oral agent
has significant myocardial depressant effects and can precipitate congestive HF and hypotension
Procainamide
used in treatment of ventricular tachyarrhythmias (less effective with atrial)
15% protein bound
2 hour elimination time
Procainamide Dose
Loading 100mg IV Q5mins until rate controlled
max: 15mg/kg
Infusion 2-6mg/min
Procainamide Side Effects
myocardial depression leading to hypotension
syndrome that resembles lupus erythematous
Check blood levels 4-8mcg/ml
Class 1C Agents are good for
Block fast Na+ channels but slow dissociation
Good for PVC and Vtach but better for atrial arrhythmias like WPW
Flecainide
effective in the treatment of suppressing ventricular PVCs and ventricular tachycardia; also atrial tachyarrthymias; WPW
oral agent
has pro-arrhythmic side effects
Propafenone
suppression of ventricular and atrial tachyarrhythmias
oral agent
has pro-arrhythmic side effects
Class 1C Agents MOA
Slow sodium channel blocker (slow dissociation) so does not vary much during the cardiac cycle
potent decrease of depolarization rate phase 0 and decreased conduction rate, with increased AP
marked inhibit conduction through the his purkinje system
Class 1B Agents MOA
fast Na+ channel blocker (fast dissociation)
alters the action potential by inhibiting sodium ion influx via rapidly binding to an blocking sodium channels (fast)
produces little effect on maximum velocity depolarization rate, but shortens AP duration and shortens refractory period
decreases automaticity
Lidocaine
used in the treatment of ventricular arrhythmias
(no longer recommended for preventing ventricular fibrillation after acute MI)
Particularly effective in suppression re-entry rhythms: ventricular tachycardia, fibrillation, PVCs
Pharmokinetics of Lidocaine
Dose: 1-1.5 mg/kg IV
Infusion 1-4 mg/min (max dose 3mg/kg)
50% protein binding
Hepatic Metabolism (active metabolism, prolongs elimination)
Metabolism affected by CYP inhibitors and inducers
10% renal elimination
extensive first pass
NOT a pro-arrhythmic b/c dissociates too quickly
Adverse Effects of Lidocaine
hypotension, bradycardia, seizures, CNS depression, drowsiness, dizziness, lightheadness, tinnitus, confusion, apnea, myocardial depression, sinus arrest, heart block, ventilatory depression, cardiac arrest and can augment pre-existing neuromuscular blockade
Mexilentine
oral agent
chronic suppression of ventricular cardiac tachyarrhythmias
cardiac clearance required
150-200mg Q8H
amine side group that allows to be adminstered oral
Can also be seen in neuropathetic pain
Phenytoin
effects resemble lidocaine class 1b agent used in suppression of ventricuar arrhythmias associated withe digitalis toxicity can also be used with other ventricular tachycardias or torsades de pointes given IV (must be saline)
dose of phenytoin
1.5mg/kg IV every 5 mins, up to 10-15 mg/kg
Therapeutic Phenytoin Blood level
10-18 mcg/ml
Pharmacokinetics of Phenytoin
metabolized in the liver
excreted in urine
elimination 1/2 time @ 24 hours
Phenytoin adverse effects
CNS disturbances, partially inhibits insulin secretion, bone marrow depression, nausea
SJS
Class 2 Agents MOA
drug induced slowing of the heart rate with resulting decreases in myocardial oxygen requirements is desirable in patients with CAD
slow speed of conduction of cardiac impulses through atrial tissues and AV node resulting in prolongation of the PR interval on EKG, increased duration of the action potential in atria
decreased automaticity
prevents catecholamine binding to beta receptors
slowing of heart rate
decrease myocardial oxygen requirements
Class 2 agents are used to treat
SVT, atrial and ventricular arrhythmias
used to suppress and treat ventricular dysrhythmias during MI and reperfusion
to treat tachyarrhythmias secondary to digoxin toxicity, and SVT (atrial fibrillation or flutter)
Propranolol
prototype
beta adrenergic antagonist
used to prevent reoccurance of tachyarrhythmias, both supraventricular and ventricular precipated by sympathetic stimulation
Onset of propanolol
2-5 minutes
Peak effect of Propanolol
10-15 minutes
Duration of Propanolol
3-4 hours
Elimination half time of propanolol
2-4 hours
Cardiac Effects of Propanolol
decreased HR, contractility, CO, increased PVR, coronary vascular resistance, however oxygen demand lowered
Metoprolol
Beta adrenergic Antagonist (selective B1)
Dose of metoprolol
5 mg IV of 5 mins
max dose: 15 mg over 20 minutes
Onset of metoprolol
2.5 minutes
1/2 life of metoprolol
3-4 hours
Metoprolol is metabolized in
liver
Is metoprolol okay to used in CHF?
Only mild cases
Esmolol
Beta adrenergic antagonist (selective B1)
Effects without decreasing BP significantly in small doses
Dose of Esmolol
0.5mg/kg IV bolus over 1 min, then 50-300 mcg/kg/min
Duration of Esmolol
less then 10 minutes
Class 3 Agents MOA
K ion channels blocked causes prolongation of cardiac depolarization and increasing action potential duration, and lengthening repolarization
decreases proportion of the cardiac cycle during which myocardial cells are excitable and thus susceptible to a triggering event
Class 3 agents treat
supraventricular and ventricular arrhythmias
can prolong QT interval and develop torsades
prophylaxis in cardiac surgery patients d/t high incidence of afib
preventative therapy in patients who have survived sudden cardiac death who are not candidates for ICD
control rhythm in afib
amiodarone
potassium, sodium, calcium channel blocker and alpha and beta adrenergic antagonist
used for prophylaxis or acute treatment in the treatment of atrial and ventricular arrhythmias (refactory SVT, refractory VT/VF, AF)
1st line drug VT/VF when resistant to electrical defibrillation
Dose of amiodarone
bolus 150-300 mg IV over 2-5 minutes, up to 5mg/kg then 1mg/hr x6 hours then 0.5mg/hr x 18 hrs
Pharmacokinetics of Amiodarone
prolonged elimination half-time (29 days) hepatic metabolism, active metabolite biliary/intestinal excretion extensive protein binding 96% large volume of distribution
Therapeutic Plasma Level of Amiodarone
1-3.5ug/ml
Adverse effects of Amiodarone
pulmonary toxicity pulmonary edema ARDs photosensitivity rashes grey/blue discolouration of skin thyroid abnormalities corneal deposits CNS/GI disturbances pro-arrhythmic effects (torsades de pointes) heart block hypotension sleep disturbances abnormal LFT 20% inhibits hepatic P450
Sotalol
Class 2 and 3 antiarrhythmic
beta adrenergic antagonist (nonselective) and potassium channel blocker
used to treat severe sustained ventricular tachycardia and ventricular fibrillation; to prevent reoccurance of tachyarrhythmias, especially aflutter and afib
excreted in urine
Side effects of sotalol
prolonged QT interval, bradycardia, myocardial depression, fatigue, dyspnea, AV block,
caution in asthmatics
Dofetilide and Ibutilide
class 3 antirrhythmics
used for conversion of afib or aflutter to NSR
used for maintenance of sinus rhythm after Afib or conversion of Afib to sinus
pro-arrhythmic
Calcium Channel Blockers are located in
cell membranes of skeletal musle vascular smooth muscle cardiac muscle mesenteric muscle neurons glandular cells
Calcium Channel blockers bind to
the receptor on voltage gated calcium ions maintaining the channels in an inactive or closed state
Calcium channel blockers
selectively interfere with inward calcium ion movement across myocardial and vascular smooth muscle cells
Calcium channel blockers are classified by:
phenyl-alkyl amines- AV node (verapamil)
Benzothiazepines-AV (diltiazem)
1,4 dyhydropyrindines-arterial beds (nifedopine)
Vascular Uses of CCBs
angina systemic hypertension pulmonary hypertension cerebral arterial spasm raynaud's disease migraine
Nonvascular Uses of CCBs
bronchial asthma
esophageal spasm
dysmenorrhea
premature labor
MOA of CCB
primary site AV node
blocks slow calcium channels, which decreases conduction through AV node and shortens phase 2 of the action potential in ventricular myocytes
contracility of the heart decreases
L type calcium channel is important in
determining vascular tone and cardiac contractility
decreased Ca keeps intracellular Ca+ low
CCB effects
decreased contractility
decrease HR
decreased activity of SA node
decreased rate of conduction of impulses via AV node
vascular smooth muscle relxation: decrease SVR and BP (arterial> venous)
CCB is used to
used in the treatment of SVT and ventricular rate control in Afib and Aflutter
Used to prevent reoccurrence of SVT
Verapamil
synthetic derivative of papaverine
Primary site of action is the AV node
Depresses the AV node
negative chronotropic effect on SA node
Clinical Uses of CCB
SVT, vasospastic angina pectoris, HTN, hypertrophic cardiomyopathy, maternal and fetal tachydysrhymthmias
premature onset of labor
Pharmacokinetic Verapamil
highly protein bound (presence of other agents such as lidocaine, diazepam, propranolol increase its activity)
Hepatic first pass metabolism and almost none of the drug appears unchanged in the urine
active metabolite, norverampil
excreted in urine and bile
Verapamil Peaks
Oral: 30-45 minutes
IV: 15 minutes
Elimination 1/2 Time of Verapamil
6-8hours
Dose of Verapamil
2.5-10mg IV over 1-3 minutes (max dose 20 mg)
Continuous gtt: 5 ug/kg/min
Do not mix verapamil with
a beta blocker
Verapamil Side Effects
myocardial depression, hypotension, constipation, bradycardia, nausea, prolongs effects of NMB
Diltiazem is a
benzothiazepines derviative
Site of Action of Diltiazem
AV node 1st line treatment of SVT HTN intermediate potency between verapamil and nifedipine minimal CV depressant effects
Clinical Uses of Diltiazem
similar to verapamil
SVT
vasospastic angina pectoris, HTN, hypertrophic cardiomyopathy, maternal and fetal tachydysrhymthmias
premature onset of labor
Dose of Diltiazem
0.25-0.35mg/kg over 2 minutes can repeat in 15 minutes
IV infusion 10mg/h
Forms of Diltiazem
PO or IV
Pharmacokinetics of Diltiazem
oral onset 15 minute
peaks in 30 minutes
70-80% protein bound/ excreted in the bile and urine (inactive metabolite)
Elimination 1/2 time: 4-6 hours
Liver disease may require a decrease dose
Side effects of Diltiazem
myocardial demand
decrease HTN
constipation
bradycardia
Nifedipine is a
dihydropyridine derviative
Clinical uses of Nifedipine
angina pectoris
Primary site of action of Nifedipine
peripheral arterioles
coronary and peripheral vasodilator properties then verpamil
little to no effect on SA or AV node
decrease SVR, BP
reflex tachycardia
can produce myocardial depression in patients with LV dysfunction or on beta blockers
Routes of Nifedipine
IV oral Sublingual
Pharmacokinetics of Oral Nifedipine
effects in 20 minutes
peaks in 60-90 minutes
90% protein bound/ hepatic metabolism, excreted in urine
Elimination 1/2 life is 3-7 hours
Side effects of Nifedipine
cancer
cardiac problems
bleeding (prolonged)
GI constipation
CCB Drug interactions Cause
myocardial depression and vasodilation with inhalation agents
can potentiate NMB
interact with calcium mediated platelet function
Verapamil and BB
potentiate HR block
Verapamil increase the risk
of local anesthetic toxicity
Verapamil and Dantrolene can cause
hyperkalemia due to slowing of inwawrd movement of K ions can result in cardiac collapse
Digoxin and CCBs
increase the plasma concentration of digoxin by decreasing its plasma clearance
H2 antagonist and CCBs
ranitidine and cimetidine alter hepatic enzyme activity and thus could increase plasma levels of CCB
Toxicity of CCB
may be reversed with IV administration of calcium or dopamine
Side Effects of CCB
vertigo headache flushing hypotension paresthesias muscle weakness can induce renal dysfunction coronary vasospasm with abrupt discontinuation
Other CCBs
clevidipine dihydropyridine potent vasodilator broken down by plasma esterases 4-6 mg/ hr IV. start at 1-2 mg/hr and titrate up to 32mg/hg
Adenosine
binds to A1 purine nucleotide receptors (activated adenosine receptors to open K+ channels and increase K+ currents
slows AV nodal conduction
used for acute Rx only
used for termination of SVT /diagnosis of VT
Dose of Adenosine
6mg IV bolus, rapid
repeat if necessary after 3 minutes, 6-12 mg IV
T1/2 of Adenosine
<10 seconds
how is adenosine eliminated?
plasma and vascular endothelial cell enzymes
Side effects of adenosine
excessive AV or SA nodal inhibition, facial flushing, headache, dyspnea, chest discomfort, nausea, bronchospasm
Digoxin
cardiac glycoside
increases vagal activity thus decreasing activity of SA node and prolongs conduction of impulses through the AV node
Decreases HR, preload and afterload
slows AV conduction by increasing AV node refractory period
positive inotrope- used to treat CHF
Pharmacokinetics of Digoxin
used for management of atrial fibrillation or flutter (controls ventricular rate), especialy withe impaired heart function narrow therapeutic index levels: 0.5-1.2ng/ml Week protein binding 90% excreted by kidneys reduce dose in elderly/ renal impairment
Dose of Digoxin
0.5-1mg divided into doses of 12-24 hours
Onset of action of Digoxin
30-60 minutes
T1/2 of digoxin
36 hours
Adverse effects of Digoxin
arrhythmias, heart block, anorexia, nausea, diarrhea, confusion, agitation
potentiated by hypokalemia and hypomagnesemia
Digoxin Toxcity treatment
phenytoin for ventricular arrthymias
pacing
atropine
Magnesium
works at sodium, potassium, calcium channels
can be used with torsaded de pointes
dose 1 gm IV over 20 minutes; can be repeated
Atropine
muscarinic receptor antagonist unstable bradyarrhythmias 0.4-1mg and repeat as neccessary metabolized by liver onset less then 1 mint DOA 30-60 minutes caution dosing < 0.4 mg-> paradoxical response
