13) Arrhythmia & Anti-Arrhythmic Drugs Flashcards
Pacemaker cells function
- Intrinsically generate rhythmic action potentials in the absence of external stimuli
Sinoatrial (SA) node
- The pacemaker
- Normal initiation site of the heartbeat/impulse (the action potential)
The impulse spreads from the SA node to the
- Atrioventricular (AV) node
- Then to the bundle of His and the Purkinje system
The SA node excites
- The right atrium
- Impulse travels through Bachmann’s bundle to excite left atrium
Arrhythmia
- Abnormality in cardiac rhythm (heart beats)
Types of cardiac cells
- Pacemaker (SA node)
- Non-pacemaker (cardiac myocytes)
Pacemaker (SA node) cell characteristics
- Exhibit Automaticity
- Intrinsically generate
APs and stimulate the heart beats without External Stimuli - Leaders/Initiators
Non-pacemaker (cardiac myocyte) cell characteristics
- Do NOT exhibit automaticity
- Receive impulses from pacemakers to generate action potential and induce contraction
- Followers/Executers
Cardiac myocyte Phase 4 (resting)
- Cardiomyocyte is −90 mV
- Maintained by slow outward leak of K+ currents
Cardiac myocyte Phase 0 (depolarization)
- An AP triggered by an impulse from pacemaker cell
- Fast Na+ channels start to open
- Na+ leaks into the cell causing depolarization
Cardiac myocyte Phase 1 (early repolarization)
- Some K+ channels open briefly
- Allow an outward flow of K+
Cardiac myocyte Phase 2 (plateau)
- L-type Ca2+ channels are open, inward current of Ca2+
- K+ leaks out
- Countercurrents are electrically balanced
- Transmembrane potential (TMP) is maintained at a plateau
Cardiac myocyte Phase 3 (repolarizaton)
- Persistent outflow of K+, now exceeding Ca2+ inflow
- Brings TMP back towards resting potential of −90 mV
- Prepares the cell for a new cycle of depolarization
The action potential in cardiomyocytes is composed of
- 5 phases (0-4)
- Begins and ends with phase 4
SA node Phase 4 (spontaneous depolarization)
- Membrane potential is -60 mV
- Ion channels open and conduct slow, inward (depolarizing) Na+ currents called “funny” currents (If)
- Transient (T-type) Ca++ channel starts to open
- Inward Ca++ currents further depolarize the cell to about -40 mV
- Second type of Ca++ channel opens (long-lasting/L-type) to depolarize the cell until AP threshold is reached (usually between - 40 and -30 mV)
SA node Phase 0 (depolarization phase of the action potential)
- Primarily caused by increased Ca++ conductance through the L-type Ca++ channels
- If and T- Ca++ currents are closed
SA node Phase 3 (repolarization)
- Occurs as K+ channels open
- At the same time, L-type Ca++ channels closes
- Once the cell is completely repolarized at about -60 mV, the cycle is spontaneously repeated
Mechanisms of arrhythmia
- Disorders in impulse formation
- Conduction block or delay
Disorders in impulse formation
- Altered automaticity
- Abnormal automaticity
Altered automaticity
- Specialized heart cells (like SA and AV nodes) possess the property of automaticity
- An increase or decrease in the activity of these cells may lead to arrhythmias
Abnormal automaticity
- Arrhythmia occurs when cardiac sites other than the SA node shows enhanced automaticity which should not possess automaticity
- Thereby, Non-Pacemaker cells exhibit abnormal automaticity “ectopic foci” and may may generate competing impulse and arrhythmia may occur
Conduction abnormalities (block or delay)
- Occur when the propagating impulse fails to conduct or conduct at slower rate
- When an impulse arrives at tissue that is still refractory, it will not be conducted
Antiarrhythmic drugs classification (Vaughan Williams Classification based on MOA)
- Class I = Na channel blockers (IA, IB, IC)
- Class II = B-blockers
- Class III = K channel blockers
- Class IV = Ca channel blockers
Class IA sodium channel blockers MOA
- During phase 0
- Greater degree of blockade in tissues that are frequently depolarizing
- Can inhibit potassium channels (Class III activity)
- Proarrhythmic
- Can slow down the conduction velocity and induce QT prolongation
Class IB sodium channel blockers MOA
- During phase 0
- Shorten phase 3 repolarization and the duration of AP
- Reduction inward Na without affecting outward K shortens AP duration
Class IC sodium channel blockers MOA
- During phase 0
- Dissociate slowly
- Minor effect on the duration of AP
Class IA drugs (names)
- Quinidine
- Procainamide
- Disopyramide
Quinidine (class IA) properties
- Alpha-adrenergic blocking activity
- Anticholinergic actions
Quinidine (class IA) special characteristics
- Can cause cinchonism blurred vision, tinnitus, headache, disorientation, and psychosis
Quinidine (class IA) metabolism
- Substrate of CYP3A4
- Inhibitor of CYP2D6
Procainamide (class IA) properties
- Anticholinergic actions
- NO alpha-adrenergic activity
Procainamide (class IA) metabolism
- Acetylated in the liver to N-acetyl procainamide (NAPA)
- Prolongs duration of the AP (QT prolongation)
- Proarrhythmic
Disopyramide (class IA) properties
- Most anticholinergic effect of this class
- NO alpha-adrenergic activity
Disopyramide (class IA) metabolism
- Substrate of CYP3A4
Disopyramide (class IA) special characteristics
- Negative inotropic effects
- May precipitate HF
- Should not be used in patients with HF
Properties shared by all class IA drugs
- Proarrythmic
- Can induce QT prolongation
- Anticholinergic adverse effects (ex: dry mouth, urinary retention, blurred vision, and constipation)
Class IB drugs (names)
- Lidocaine
- Mexiletine
Lidocaine (class IB) metabolism
- First pass so only given IV
Lidocaine (class IB) characteristics
- High safety profile
- Least cardiotoxic agent among sodium channel
blockers - No negative inotropic effect
Lidocaine (class IB) side effects
- CNS side effects that often limit the duration of continuous infusions
- Nystagmus (early indicator of toxicity)
- Drowsiness
- Slurred speech
- Paresthesia
- Agitation
- Confusion
- Convulsions
Mexiletine (class IB) metabolsim
- Oral
- Narrow therapeutic index
Mexiletine (class IB) most common side effecs
- Nausea
- Vomiting
- Dyspepsia
Class IC drugs (names)
- Flecainide
- Propafenone
Flecainide (class IC)
- Substrate of CYP2D6
- Well tolerated
Flecainide (class IC) side effects
- Blurred vision
- Dizziness
- Nausea
Propafenone (class IC)
- Substrate of CYP2D6
- B-blocking effects
Propafenone (class IC) side effects
- Blurred vision, dizziness, and nausea
- Bronchospasm due to its β-blocking effects
- Should be avoided in patients with asthma
β-Blockers reduce arrhythmia by
- Blocking B-adrenergic receptors
- Antagonizing the increased sympathetic tones and high levels of circulating catecholamines (NE and epinephrine)
β-Blockers reduce phase 4 spontaneous depolarization through
- Reducing automaticity at SA node and decreasing the heart rate
- Reducing AV nodal conduction
Metoprolol is a selective β-1 receptor blocker widely used in
- Treatment of cardiac arrhythmias
- Reduces the risk of bronchospasm compared to nonselective β-blockers
- CYP2D6 substrate
Esmolol is a very-short-acting selective β-1 receptor blocker used for
- IV administration in acute arrhythmias that occur during surgery or emergency situations
Esmolol has a fast onset of action and a short half-life, making it ideal for
- Acute situations
- Limiting its adverse effect profile
Class III drugs diminish
- Outward potassium current during the repolarization phase
Class III drugs prolong
- Duration of AP without altering phase 0 of depolarization or the resting membrane potential
All class III drugs have the potential to
- Induce arrhythmia
Amiodarone and dronedarone
- Both have beta blocker (class II) and calcium channel blocker (class IV) actions on the SA and AV nodes
- Decreases the heart rate and conduction
Sotalol
- Class III antiarrhythmic agent
- Also has potent nonselective β-blocker (class II) activity
Ibutilide MOA
- Reduces repolarization (phase 3)
- Prolongs the duration of action potential through
Ibutilide prolongs the duration of action potential through
- Inhibiting/blocking potassium channels
- Activating the slow inward sodium current during phase 2
Class III K channel blockers (names)
- Amiodarone
- Dronedarone
- Sotalol
- Dofetilide
- Ibutilide
Amiodarone (class III) metabolism
- Prolonged half-life of several weeks
- Distributes extensively in adipose tissue
Amiodarone (class III) is a substrate of
- CYP3A4
Amiodarone (class III) is an inhibitor of
- CYP1A2
- CYP2A4
- CYP2C9
- CYP2D6
Amiodarone (class III) characteristics
- Iodine moiety in its structure (structurally related to thyroxine)
- May cause thyroid dysfunction (hypo or hyperthyroidism)
Amiodarone (class III) drug interactions
- Drugs that induce QT prolongation, class I (quinidine)
- Concomitant use of drugs that have depressant effects on the heart (B-blockers (propranolol), verapamil (CCB)) can precipitate bradycardia and cardiac arrest, sinus arrest and AV block
- CYP3A4 inhibitors (ketoconazole, grapefruit juice, verapamil), increase plasma concentration of amiodarone, and consequently can precipitate arrhythmia
Dromedarone (class III) metabolism
- First pass effect
- Bioavailability increased by food
- Less lipophilic, has lower tissue accumulation, and has a shorter serum half- life than amiodarone
Dromedarone (class III) is a substrate of
- CYP3A4
Dromedarone (class III) is an inhibitor of
- CYP3A4
- CYP2D6
Dromedarone (class III) side effects
- Liver injury
- QT prolongation
Dromedarone (class III) drug interactions
- Drugs that induce QT prolongation
- Verapamil (CCBs) and B-blockers can cause Cardiac block
- Digoxin increases risk of arrhythmia and cardiac arrest
- Digoxin potentiate the dronedarone induced decrease in AV node conduction
- CYP3A4 inhibitors/inducers affect dronedarone
Solatol (class III) metabolism
- Not metabolized
- Not inhibited or induced any CYP450 enzymes
- Excretion of sotalol is predominantly via the kidney unchanged
Solatol (class III) side effects
- Life threatening arrhythmia
- QT prolongation
Solatol (class III) drug interactions
- Antiarrhythmics drugs (e.g., Amiodarone)
- May precipitate arrhythmia and QT prolongation. Calcium channel blockers (e.g., verapamil) and B- blockers (e.g., propranolol)
- AV conduction block, bradycardia, cardiac arrest and hypotension adverse effects associated with β-blockers
Dofetilide (class III) metabolism
- Excreted unchanged in the urine
Dofetilide (class III) side effects
- Box warning proarrhythmia serious arrhythmia (torsade de pointe)
Ibutilide (class III) metabolism
- First-pass metabolism
- Not used orally
Ibutilide (class III) side effecs
- High risk of QT prolongation and proarrhythmia
Ibutilide (class III) characteristics
- Does NOT have sodium blocking (class I), antiadrenergic (B- blocking, class II) or calcium blocking (class IV) activities
Class IV CA channel blockers
- Block L-type calcium channels in firing cells
SA/AV nodes - Slow down phase 0 depolarization rate
- Slow down the spontaneous depolarization of phase 4
Class IV Ca channel blockers activity lead to
- Reduction in automaticity in SA node
- Reduction in AVN conduction and prolongation the effective refractory period
Class IV drugs (names)
- Verapamil
- Diltiazem
Verapamil and Diltiazem (class IV) metabolism
- Substrates and inhibitors of CYP3A4
Verapamil and Diltiazem (class IV) drug interactions
- B-blockers (e.g., propranolol, sotalol)
- Cardiac block
- Statins (simvastatin) and other CYP3A4 substrates
- Plasma concentration increased
- Grapefruit juice may increase plasma levels of verapamil
Verapamil and Diltiazem (class IV) side effects
- Peripheral vasodilatation, ‘negative inotropic effects
- Extracardiac effects include constipation, lassitude, nervousness and peripheral edema
Digoxin increases
- Vagal efferent activity to the heart
- Mechanism that is not understood
Parasympathomimetic action of digoxin
- Reduces sinoatrial (SA) firing rate (decreases heart rate; negative chronotropy)
- Reduces conduction velocity of electrical impulses through the atrioventricular node
Increase in vagal tone in the heart induced by digoxin will reduce
- Automaticity in SA node
- Conductivity in AV node
Digoxin increases the vagal tone in the heart, and consequently this will
- Reduce automaticity in SA node (SA node)
- Reduce the AV nodal conduction (AV node)
- Correct for arrhythmia
Digoxin is often used in the treatment of patients with
- Heart failure who have arrhythmia
- Most other drugs that can be used to achieve this goal have undesirable negative inotropic side effects (e.g. beta blockers and calcium channel blockers
Adenosine
- Nucleoside that occurs naturally throughout the body
- Half-life in the blood is less than 10 seconds
Adenosine MOA
- Activation of K+ current
- Inhibition of calcium current
- Results in a marked hyperpolarization
and suppression of calcium dependent action potentials in SA & AV nodes
Given as an IV bolus dose, Adenosine directly
- Inhibits AV nodal conduction
- Has lesser effects on the SA node
Magnesium sulfate
- Slows the rate of SA node impulse formation
- Prolongs conduction time along the myocardial tissue
