antiarrhythmic...
TRANSCRIPT
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Antiarrhythmic Drugs
Munir Gharaibeh MD, PhD, MHPE
Faculty of Medicine,
The University of Jordan
October 2014
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Types of Cardiac ArrhythmiasAbnormalities of Impulse Formation:
Rate disturbances.
Triggered automaticity.
Abnormalities of Impulse Conduction:
Blocks.
Reentry.
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11/17/2014 3Munir Gharaibeh MD, PhD, MHPE
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Ion Permeability Changes Potential Changes Genes and Proteins
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Causes of Cardiac ArrhythmiasCardiac Causes:
Ischemic heart disease.
Inflammation.
Trauma e.g. heart surgery.
Congestive heart failure.
Hypotension.11/17/2014 5Munir Gharaibeh MD, PhD, MHPE
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Causes of Cardiac Arrhythmias
Non Cardiac Causes:
Electrolyte imbalance.
Acid-Base imbalance.
Hypoxia.
Drugs: Digitalis, Anesthetics, Tricyclic, Diuretics, Bronchodilators.
G.I. reflexes.
Neural reflexes.
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Na+ channels cycling through different conformational states during the cardiac
action potential
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11/17/2014 8Munir Gharaibeh MD, PhD, MHPE
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11/17/2014 9Munir Gharaibeh MD, PhD, MHPE
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Normal Circuitry
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Re-entry Rhythm
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11/17/2014 12Munir Gharaibeh MD, PhD, MHPE
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11/17/2014 13Munir Gharaibeh MD, PhD, MHPE
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Pre-requisites for Reentry
(Circus Movement)
Anatomic or physiologic obstacle.
Unidirectional block.
Conduction time around the circuit must be
longer than the effective refractory period.
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Molecular and Genetic Basis of some Cardiac Arrhythmias
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ECG of some Arrhythmias
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Torsade de Pointes
Polymorphic Ventricular Tachycardia
LQT, syncope, and sudden death.
Causes:
Familial long QT interval
Drug - Induced (drugs which prolong APD)
Mechanisms:
Increased inward current (GF), or
Decreased outward (LF) current during the plateau.
Genetic Studies:
300 different mutations in at least 8 ion channel genes.
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11/17/2014 18Munir Gharaibeh MD, PhD, MHPE
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Torsade de PointesRisk Factors:
Bradycardia.
Hypokalemia.
Triggered upstrokes.
Drugs which APD.
Treatment:
K+
Triggered upstrokes ( Blockers or Mg++)
APD (Pacemaker or isoproterenol).
www.sads.org
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Other Congenital ArrhythmiasShort QT Syndrome:
– GF mutations in three potassium channel
genes(KCNH2, KCNQ1, and KCNJ2).
Chatecholaminergic Polymorphic
Ventricular Tachycardia (CPVT):
– Stress or emotion-induced syncope.
– Caused by mutations in sarcoplasmic proteins
that control calcium.
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Other Congenital ArrhythmiasSick Sinus Syndrome:
– Mutations in HCN4 and SCN5A
Brugada Syndrome:
– Ventricular fibrillation, persistent ST elevation,
and BBB.
– Linked to LF mutations in SCN5A
Familial Atrial Fibrillation:
– Linked to GF mutation in the potassium
channel gene, KCNQ1.
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Nonpharmacologic TherapySurgery.
Radiofrequency Catheter Ablation.
Implantable Cardioverter- Defibrillator (ICD).
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Mechanism of Action of Antiarrhythmic Drugs
Readily bind to activated channels or inactivated
channels, but bind poorly to rested channels.
i.e.: Use –Dependent or State-Dependent.
Channels in normal cells will rapidly lose the
drug from the receptors during the resting
portion of the cycle.
This selectivity is lost with increasing doses,
leading to drug-induced arrhythmias.
Also, these drugs may become” Proarrhythmic or Arrhythmogenic” during fast heart rates,
acidosis, hyperkalemia, or ischemia.
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ways to reduce the rate of spontaneous discharge ways to reduce the rate of spontaneous discharge
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Possible Effects of the Drugs on Action Potential
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Class 1A Drugs
Quinidine:
Prototype, Antimalarial.
Cinchona tree Antipyretic.
Inhibits and muscarinic receptors.
Slows upstroke, conduction, and
prolongs APD and QRS duration.
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Quinidine
Use restricted to patients with normal
hearts( no failure, no ischemia), but
have atrial or ventricular arrhythmias.
Occasionally used in acute severe
malaria.
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Quinidine
Side Effects:Nausea (18%), Diarrhea (33%).
Headache, Dizziness, and tinnitus= CinchonismHypersensitivity, fever, rash, angioedema.
Thrombocytopenia.
Excessive prolongation of QT interval, slowed conduction and sudden death (TdP).
Hypotension.
Serum Digoxin levels.
Warfarin effects.
Sudden death.
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Class 1A Drugs
Procainamide:
Oral, but has short t½.
L.E. (30% of patients Tx over 6
moths)
Acetylated NAPA (Class III) action
Disopyramide
More anticholinergic effects but less
diarrhea than quinidine
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Class 1B DrugsLidocaine:
High affinity to bind with activated and
inactivated Na+ channels with rapid
kinetics.
Acts selectively on ischemic tissue to
promote conduction & block reentry.
More effective with K+.
Not effective in atrial arrhythmias.
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Class 1B DrugsLidocaine:
Kinetics:
Well absorbed, but ineffective orally, due to first pass effect.
Well distributed, including the brain.
Side Effects:
Least cardiotoxic of the class, except for hypotension with high doses due to
depression of the myocardium.
CNS: parasthesia, tremor, nausea, slurred speech, and convulsions.
Was routinely given to all MI patients to prevent ventricular arrhythmias.
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Class 1B Drugs
Tocainide:
Oral analog of lidocaine.
CNS, GI and blood dyscrasia.
Mexiletine:
Oral analog of lidocaine.
Neurologic side effects.
Phenytoin:
Digitalis induced arrhythmias.
Epilepsy.
Congenital heart surgery.
Congenital prolonged QT interval. 11/17/2014 35Munir Gharaibeh MD, PhD, MHPE
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Class 1C Drugs
Flecainide:
Potent blocker of Na + and K+ channels.
Negative inotropic effect.
Proarrhythmic ventricular.
Effective in supra ventricular
tachycardia with normal hearts.
Side Effects: Ventricular arrhythmias,
CNS, and sudden death.
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Class 1C Drugs
Propafenone:
Blocks Na+ channels but also has
some Beta blocking and Ca++
blocking activity.
No effect on QT interval.
Used for supraventricular
arrhythmias.
Side effects: metallic taste,
constipation, and arrhythmias.11/17/2014 37Munir Gharaibeh MD, PhD, MHPE
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Class II DrugsPropranolol:
Besides beta blocking, membrane
stabilization, and intrinsic sympathmimetic
activities, has effective antiarrhythmic
activity
Very effective, well tolerated, and
documented to reduce mortality after acute
myocardial infarction by reducing
arrhythmias.
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Class II DrugsEsmolol:
Short acting, used in intraoperative and
acute arrhythmias
β1 selective
No membrane stabilization effect.
Acebutolol:
Short acting, used in intraoperative and
acute arrhythmias.
β1-selective.
Also has direct membrane stabilizing.11/17/2014 39Munir Gharaibeh MD, PhD, MHPE
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Class III Drugs
Amiodarone:
Blocks K+ channels and markedly prolongs APD.
Class I actions.
Blocks and Receptors.
Ca++ blocking actions.
Reserved for life-threatening atrial and ventricular arrhythmias.
Only slows heart rate and AV conduction.
Low incidence of TdP despite significant QT prolongation.
Peripheral vasodilator (only with IV). 11/17/2014 40Munir Gharaibeh MD, PhD, MHPE
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Class III DrugsAmiodarone:
Given IV (Loading dose 10gm) and orally.
Slow kinetics (t½ 25-110 days), metabolized by CYP3A4 enzymes.
Toxicity: mainly extracardiac and dose related.
Lung fibrosis (1%).
CNS.
Thyroid( hypo and hyper).
GI and liver.
Corneal deposits,
Skin (photodermatitis and discoloration).
Digoxin & Anticoagulants.
Interactions: affected by CYP3A4 activity and can inhibit other enzymes.11/17/2014 41Munir Gharaibeh MD, PhD, MHPE
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Class III DrugsSotalol:
Beta blocker and Class III actions.
Atrial and ventricular arrhythmias.
Bradycardia, HF, Prolongation of QT.
Bretylium Tosylate:
Originally an antihypertensive, but tolerance develops.
Releases NE, then Release / Reuptake
Rarely used except in the prevention of ventricular fibrillation after cardiversion and lidocaine.
Hypotension, Parotid swelling.
Ibutilide.
Dofetilide.
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Class IV Drugs
(Ca++ Channel Blockers)
Verapamil
DiltiazemBlock activated and inactivated L-type Ca++
channels.
Effects more marked in tissues that fire frequently, less completely polarized at rest and those dependant on Ca++ (SA node and AV node).
Paroxysmal Supraventricular Tachycardia.Vasodilators and have negative inotropic effects.
Can cause severe AV block in diseased hearts.
Safe: Constipation, gastric discomfort, vertigo, headache, nervousness, pruritis.
Digoxin levels.
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Properties of Several Recognized Voltage-Activated Calcium Channels.
Type Channel
Name
Where Found Properties of
the Calcium
Current
Blocked By
L CaV1.1–
CaV1.3
Cardiac, skeletal, smooth muscle,
neurons (CaV1.4 is found in retina),
endocrine cells, bone
Long, large, high
threshold
Verapamil,
DHPs,
Cd2+, -aga-
IIIA
T CaV3.1–
CaV3.3
Heart, neurons Short, small, low
threshold
sFTX,
flunarizine,
Ni2+,
mibefradil1
N CaV2.2 Neurons, sperm2 Short, high
threshold
Ziconotide,3 g
abapentin,4
-CTX-
GVIA, -aga-
IIIA, Cd2+
P/Q CaV2.1 Neurons Long, high
threshold
-CTX-
MVIIC, -
aga-IVA
R CaV2.3 Neurons, sperm2 Pacemaking SNX-482, -
aga-IIIA
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Miscellaneous Drugs
Digoxin:
Old fashioned agent for atrial
arrhythmias.
Direct Actions.
Vagotonic Effects.
AV refractoriness.
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Miscellaneous Drugs
Magnesium:
Works on Na+/K+ ATPase, Na+ channels, certain K+ channels and Ca++ channels.
Effective IV in refractory digitalis- induced ventricular arrhythmias only in hypomagnesemicpatients.
Also, in TdP patients even if serum Mg++ is normal.
Potassium salts:
For digitalis- induced arrhythmias with hypokalemia.
Depress ectopic pacemakers and slow conduction.
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Miscellaneous Drugs
Adenosine:
Naturally occurring nucleoside.
Activates inward rectifier K+ current and
inhibits Ca++ current.
Very short acting (t 1/2 10 seconds).
Phase 4 depolarization in SA node.
AV conduction.
No effect on ventricles.
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Miscellaneous Drugs
Adenosine:
90-95% effective in supraventricular
tachycardia.
Less effective in the presence of
adenosine receptor blockers, e.g.
theophylline and caffeine.
Can cause very short –lived flushing
(20%), chest tightness, AV block,
headache, hypotension, nausea, and
parasthesia. 11/17/2014 50Munir Gharaibeh MD, PhD, MHPE
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Afterdepolarizations
(Triggered Automaticity)
Require a normal action potential for their initiation.
Early Afterdepolarizations (EAD):
– Interrupt phase 3.
– Exacerbated at low heart rates.
– Contribute to development of long QT-related
arrhythmias.
Delayed Afterdepolarizations (DAD):
– Occur with increased intracellular calcium.
– Exacerbated by fast heart rates.
– Responsible for arrhythmias of digitalis,
catecholamines, and ischemia.11/17/2014 52Munir Gharaibeh MD, PhD, MHPE
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11/17/2014 53Munir Gharaibeh MD, PhD, MHPE