Cardiac Antidysrhythmic Drugs Flashcards
Phase 0 of Cardiac Myocyte Action potential
1) Rapid depolarization
2) Inflow of Na+ due to opening of fast Na+ channels
3) Duration - 3 to 5 msec
Phase 1 of Cardiac Myocyte Action potential
1) Partial repolarization
2) Inward Na+ current deactivated
3) Outflow of K+
Phase 2 of Cardiac Myocyte Action potential
1) Plateau
2) Slow inward Ca2+ current balanced by outward K+ current
Phase 3 of Cardiac Myocyte Action potential
1) Repolarization
2) Calcium current inactivates
3) K+ outflow
Phase 4 of Cardiac Myocyte Action Potential
1) Resting membrane potential
2) Na+ efflux and K+ influx via Na/K-ATPase pump
On which phase of the cardiac myocyte action potential do the following cardiac anti-dysrhythmic drugs work:
1) Class I Agents
2) Class II and IV Agents
3) Class III Agents
1) Class I Agents - Phase 0
2) Class II and IV Agents - Phase 2
3) Class III and 1A Agents - Phase 3
Absolute Refractory Period
1) Phase 0 to 2 and early part of 3
2) Time period where the cell CAN NOT depolarize again
3) Cardiac Myocytes are “fast response tissue”
Approximately how much time passes during the action potential of a myocyte?
~300msec (phase 0 = 3-5msec, phase 1 and = 175msec, phase 3 = 75msec)
Phase 4 of the Cardiac Pacemaker (Nodal) Cell action potential?
1) Spontaneous depolarization to threshold
2) Diffusion of K+ out of cell ↓
3) Na+ into influx ↑
4) During the last 1/3 of phase 4, Ca2+ influx begins
Phase 0 of the Cardiac Pacemaker (Nodal) Cell action potential?
1) Slow depolarization
2) Ca2+ diffuses into cell and slight Na+ influx
Phase 3 of the Cardiac Pacemaker (Nodal) Cell action potential?
1) Depolarization
2) K+ diffuses out of cell
3) Pacemaker cells are slow response tissue
Cardiac Nodal tissue’s (SA and AV node) depolarization is primarily controlled by what and are consequently referred to as what?
Cardiac Nodal tissue’s (SA and AV node) depolarization are largely controlled by Ca2+ channels currents and are referred to as slow response tissue.
3 MOAs of Cardiac Antiarrhythmic Drugs?
1) Blocking the Na+, K+, or Ca2+ channels in the heart
2) ↓ Automaticity
3) Alter the re-entrant circuit
Antiarrhythmic Drugs whose mechanism of action is to ↓ Automaticity can work in which 4 different ways?
1) ↓ Phase 4 depolarization
2) ↑ Threshold potential
3) ↑ Max diastolic potential
4) ↑ Action potential duration
Vaughn Williams classification of Antiarrhythmic Drugs?
1) Class 1 - Fast Na+ channel blockers
2) Class 2 - Beta-adrenergic blockers(“beta blockers”)
3) Class 3 - K+ channel blockers
4) Class 4 - Non-Dyhydropiridine Ca2+ channel blockers
Class 1A Antiarrhythmic Drugs?
1) Quinidine
2) Procainamide
3) Disopyramide
Class 1B Antiarrhythmic Drugs?
1) Lidocaine
2) Mexiletine
3) Phenytoin
Class 1C Antiarrhythmic Drugs?
1) Flecainide
2) Propafenone
Class 2 Antiarrhythmic Drugs?
1) Esmolol, Acebutalol
2) Propanolol, Metoprolol
Class 3 Antiarrhythmic Drugs?
1) Amidodorone
2) Dronedarone
3) Dofetilide
4) Ibutilide
5) Sotalol
Class 4 Antiarrhythmic Drugs?
1) Verapamil
2) Diltiazem
What are 4 Antiarrhythmic drugs that do not fit into the Vaughn Williams Classification?
1) Digoxin
2) Adenosine
3) Magnesium
4) Ivabradine (Corlanor)
Class 1 Antiarrhythmic characteristics?
1) ↓ Phase 0 of the fast action potential (aka ↓ Vmax)
2) Slows conduction velocity in atria, ventricles and His-Purkinje fibers
3) ↓ Automaticity
Class 2 Antiarrhythmic characteristics?
1) ↓ Automaticity by ↓ phase 4 spontaneous depolarization of SA node
2) Negative Dromotrope
3) Negative Chronotrope
4) Negative Inotrope
Explain the following terms:
1) Dromtrope
2) Chronotrope
3) Inotrope
1) Dromtrope - Automaticity or speed of conduction
2) Chronotrope - Heart rate
3) Inotrope - Contractility
Class 3 Antiarrhythmic characteristics?
1) Prolongs repolarization (Phase 3)
2) Prolongs QT
3) Prolongs effective refractory period
Class 4 Antiarrhythmic characteristics?
1) Only includes Verapamil and Diltiazem
2) Slow influx of Ca2+ at L-type voltage-gated Ca2+ channels
3) ↑ Threshold voltage resulting in ↓ amount of Ca2+ entry into nodal cell
4) Negative dromotrope
5) Negative chronotrope
6) Negative Inotrope
Which non anti-arrhythmic effect of Class 4s is important to remember?
Class 4s also inhibit Ca2+ entry into vascular smooth muscle tissue such as those in coronary arteries and systemic arteries - this results in hypotension.
Explain Use-Dependence aka Rate Dependence and how it relates to Class 1 drugs
1) All Class 1s have an affinity for a particular state of the Na+ channel they block.
2) Either affinity during activation and or inactivation
3) Class 1’s affinity are greatest at fast HRs and least during slow HRs (Its better at lowering a HR of 200 than it is at lowering a HR of 95)
Class 1A Anti-arhythmics are used to treat which Heart rhythms?
1) SVTs
2) Ventricular Arrhythmias
Quinidine Characteristics
1) Class 1A with affinity for open state only
2) Blocks K+ also (class 3 effect)
3) Also has alpha-adrenergic antagonist and vagolytic effects
4) Prolongs QRS and QT
Quinidine Clinical Use
1) Used for A-fib conversion and maintenance of NSR
2) Used for SVT associated with WPW syndrome
3) Used as an Antimalarial drug
4) IV form rarely used due to vasodilation and myocardial depression
Quinidine Metabolism
1) Hepatic, via CYP 3A4
2) Has an active metabolite that is also point at blocking Na+ channels
3) 80 to 90% protein bound to albumin
4) ~20% excreted in kidney as unchanged drug
Quinidine Side Effects
1) Diarrhea (most common)
2) Prolongs QT-interval in a dose-dependent fashion
3) Torsades de Pointes
4) Syncope (PO)
Quinidine Drug interactions
1) Prolongs non-depolarizing and depolarizing neuromuscular blockers
2) ↑ Digoxin and Warfarin concentrations
3) CYP 3A4 inducers such as phenobarbital, phenytoin, rifampin ↓ Quinidine concentrations
4) CYP 3A4 inhibitors such cimetidine, ↑ Quinidine concentrations
Procainamide Characteristics
1) Class 1A with affinity for open state only
2) Blocks K+ also (class 3 effect)
3) Has very weak anticholinergic effects
4) Not as effective in treating A-fib/A-flutter as Quinidine is
5) Prolongs, QT, QRS and
Procainamide dosing for urgent Tachycardia and A-fib conversion?
1) Tachycardia conversion - 100mg IV Q5min until ~15mg/kg given or QRS widens > 50%
2) Afib - 1gm IV for 30mins then 2mg/min
Which clinical consideration should be noted in PTs who have been cardio converted with Procainamide?
Procainamide is no longer available in oral dosage form, so tif converted with IV form, they will have to be put on a different oral agent to maintain their SR.
Procainamide Metabolism
1) Eliminated by renal and hepatic metabolism
2) Hepatic metabolism via N-acetyl transferase enzyme
3) Active metabolite is NAPA (N-acetyl procainamide)
Why should you adjust the dosage of Procainamide in renal patients?
Because both Procainamide and its metabolite (NAPA) are excreted via the kidneys.
NAPA (N-acetyl-Procainamide) Characteristics
1) Has Class 3 Anti-arrhythmic effects
2) Does not have Na+ blocking effects like Procainamide
3) Has a longer half-life than Procainamide
4) Can cause Torsades de Pointes with excessive build-up
Why is the use of Procainamide limited during general anesthesia?
Rapid IV injection is contraindicated because it causes hypotension
Chronic administration of Procainamide is associated with which two adverse effects?
1) A lupus erythematosus-like syndrome
2) Positive ANA (Anti- Nuclear Antibody) test
Procainamide Drug Interactions
1) ↑ Effect of non-depolarizing and depolarizing neuromuscular blockers, lidocaine, and skeletal muscle relaxants
2) Cimetidine, ranitidine, beta-blockers and amiodarone ↑ Procainamide and NAPA levels
3) Trimethoprim ↑ NAPA levels
Procainamide should not be administered to PTs with allergy to which type of meds?
Procaine (ester-type) local anesthetics
Disopyramide Characteristics
1) Class 1A
2) Blocks K+ also (class 3 effect)
3) Has very strong anticholinergic (vagolytic) effects
4) DOES NOT posses alpha-adrenergic antagonist activity
5) Most common side effect is dry mouth to the point of bleeding and urinary retention
Class 1B Agents Characteristics
1) Less potent Na+ channel blockers compared to 1A and 1C Agents
2) Works best on diseased tissue i.e. ischemia
3) More effective in Ventricular rhythms than SVTs (not effective against A-fib and A-flutter)
What MOA is present in Class 1B agents that isn’t present in 1A and 1C
Class 1B agents ↓ (shortens) the ERF and action potential duration in normal ventricular muscle.
Lidocaine Characteristics
1) Class 1B agent
2) Local anesthetic agent as well IV Tx for Ventricular Rhythms
3) Used tin Tx of PVCs and V-tach
4) Not useful in Tx of Atrial arrythmias
5) Can be used as an alternative to amiodarone in pulseless V-tach
What is an advantage to using Lidocaine over Procainamide and Quinidine?
Lidocaine has a faster onset of action and short half-life, which allows for easy titration
Lidocaine Dosage in PTs with normal hepatic function
1) IV - 2mg/kg followed by continuous infusion of 1 to 4 mg/min CI
2) IM - 4 to 5mg/kg
Lidocaine Pharmacologic actions
1) Improves AV conduction
2) Action potential and ERF is shortened
Lidocaine Dosage in Pulseless VT/VF Conversion or VT with a pulse
1) 1 to 1.5mg/kg IV bolus, then repeat 0.5-0.75 mg/kg q 3-5 mins (Maximum of 3mg/kg)
2) If LVEF < 40% then give 0.5 to 0.75 mg/kg IVP
Lidocaine Dosage in Pulseless VT maintenance
1 to 4 mg/min CI
Explain why conditions that ↓ CO or Liver blood flow can ↑ lidocaine toxicity.
Because of the rapid rate at which Lidocaine is metabolized in the liver, and conditions that ↓ CO or liver blood flow can decrease lidocaine clearance, which ↑ toxicity.
What are some examples of conditions that can ↑ Lidocaine toxicity?
1) Anesthesia
2) Acute MI
3) CHF
4) Shock or any surgical procedures that ↓ CO or liver blood flow
Lidocaine Adverse Effects of CNS
- Symptoms of CNS stimulation occur with doses > 5μg/mLand includes:
1) Seizures
2) Nystagmus (early sign)
3) Parasthesias and disorientation
4) Drowsiness, tinnitus, slurred speech,
5) Muscle twitching and tremors
Lidocaine Adverse Effects that are non CNS related
1) Hypotension
2) Bradycardia
3) Prolonged PR interval, and widening of the QRS may occur in toxicity
Lidocaine Adverse Effects when dosage > 10μg/mL
1) CNS depression, apnea and cardiac arrest
Which parameters are necessary to monitor during Lidocaine Continuous Infusions and why?
Arterial hypoxemia, hyperkalemia, and acidosis because the convulsive threshold for lidocaine are decreased in these states
Effects of Lidocaine when given at the same time as NMBs and NDNMBs?
Enhances neuromuscular blockade of DNMBs and NDNMBs?
Effects of Lidocaine when given at the same time as Beta blockers such as Propranolol and or Cimetidine?
Reduces hepatic flow and thus decreases Lidocaine clearance, which increases Lidocaine levels and chance for CNS effects such as seizures
Mexiletine (Mexitil) Characteristics
1) An orally active amine analog of Lidocaine - structurally modified to reduce 1st pass effect metabolism
2) Used for Tx of acute or chronic V-Tach
3) Major adverse effects include tremor and nausea
4) Other side effects include ataxia, nystagmus, vertigo, slurred speech
Phenytoin Metabolism
Liver, specifically CYP 450
Phenytoin exhibits Michaelis-Mentin Pharmokinetics, what does that mean?
Michaelis-Mentin Pharmokinetics is a type of non-linear pharmacokinetics where phenytoin’s metabolism is saturable
Phenytoin (Dilantin) Clinical use
1) Supresses V-Tach and Torasades de Pointes
2) Rarely used any more, primarily used as an anti-convulsant
Phenytoin (Dilantin) dose
1) 100mg IV q5mins (1.5mg/kg) or 10 to 15 mg/kg (1000mg max)
Why can’t you mix Phenytoin with D5W?
It will precipitate, use NaCl instead
What is the Max infusion rate of of Phenytoin? what will happen if infused faster than that?
Max infusion rate = 50mg/min, infusing faster than that can cause profound myocardial depression
Class 1C Characteristics?
1) Most potent anti-arrhythmic at slowing conduction velocity of the cardiac impulse and decreasing the rate of phase 0 depolarization
2) Dissociate slowly from Na+ channels
3) Potent negative inotropes
Class 1C agents are ABSOLUTELY CONTRAINDICATED in which PTs and why?
Class 1C is absolutely contraindicated in PTs structural heart disease (i.e. previous MI) due to increased mortality rates based on results from the CAST trial.
Flecainide (Tambacor) Characteristics?
1) Class 1C fluorinated local anesthetic analog of Procainamide
2) Blocks Na+ channels in the “open” state only
3) Posses local anesthetic effects
EKG effects of Flecainide (Tambacor)
Prolongs PR and QRS, and QT intervals
Flecainide (Tambacor) adverse effects
1) Dizziness and visual disturbances (most common)
2) Proarrhythmic effects
3) 1st degree heart block
Flecainide (Tambacor) Clinical Use
1) More effect in suppressing Ventricular rhythms than Quinidine and Disopyramide
2) Tx of WPW syndrome, PVCs, and Paroxysmal A-fib/flutter
Propafenone (Rhythmol) Clinical use?
Tx of Ventricular and atrial rhythms
Propafenone (Rhythmol) Pharmacologic actions?
1) Blocks Na channels in both the open and inactivated states
2) Has weak Beat-blocker properties since it’s structurally similar to BBs
3) Also possesses Calcium channel blocking effects
EKG effects of Propafenone (Rhythmol)
Prolonged PR and QRS
Propafenone (Rhythmol) Metabolism
1) Metabolized by liver following nonlinear pharmacokinetics
2) Has pharmacologically active metabolites
Propafenone (Rhythmol) Adverse effects?
1) Unusual/altered taste, dizziness, N and V, and vertigo (most common)
2) 1st degree block or PVCs
Why are Propafenone (Rhythmol) avoided in PTs with bronchospastic disorders like COPD and asthma?
Because they are non-selective beta blockers
Effects of Class 1 Anti-arrythmics on ERP and action potential duration?
1) Class 1A - ↑ERP, ↑ APD
2) Class 1B - ↓ERP, ↓APD
3) Class 1C - little to no effect on ERP and APD
Amiodarone Characteristics?
1) K+ channel blockade (Class 3)
2) Also has Na+, Beta, and Ca2+ blockade properties
1) Structural analog of the thyroid hormone (heroine)
2) Highly lipophillic, concentrated in many tissues, and is excreted slowly
4) Highly protein bound (96%)
(T/F?) Amiodarone possess electrophysiologic characteristics from all 4 Vaughn Williams classes?
True - While its primarily a K+ channel blockade, it also blocks Na+, Beta, and Ca2+ as well
Amiodarone Pharmacological effects?
1) ↑ Action potential duration which ↑refractoriness (Phase 3).
2) ↓ Conduction velocity and ↓ SA and AV node automaticity
3) Prolongs PR, and QT and widens QRS, and
4) Negative chronotrope
5) Slows Phase 2 cardiac action potential
6) Dilates coronary arteries and ↑ coronary blood flow
7) Does not require adjustments for hepatic, renal, or cardiac dysfunction
Amidarone Clinical Uses
1) SVT and Ventricular rhythms
2) Pre-op administration ↓ A-fib after cardiac surgery
3) Conversion and maintenance of sinus rhythm in paroxysmal atrial fibrillation
Amiodarone Pharmacokinetics
1) Onset - 8 to 24 hours
2) Peak - 1 week to 5 moths
3) Duration after DC of med. - 7 to 50 days
4) Half Life - ~4- o 58 days
Amiodarone Metabolism
1) Liver: primarily via CYP 3A4
2) Active metabolite: N-desethylamiodarone (DEA), which has similar effects to Amiodarone
Amiodarone Adverse Reactions?
1) Pulmonary Fibrosis, which can be fatal (most serious )
2) Pulmonary toxicity with doses > 400mg/day
Anesthetic Considerations for the PT on Amiodarone
Use lowest O2 concentration possible during anesthetic delivery prevent the formation of free O2 radicals
Amiodarone Cardiovascular Side Effects
Bradycardia, heart block, Torsades de Pointes,
Amiodarone’s role in GI and Liver toxicity
- Elevates hepatic transaminases (ALT, AST, and GGT) and alkaline phosphatase
- N and V, and anorexia are common with PO doses
Amiodarone’s role in GI and Thyroid toxicity
1) Contains 2 iodine molecules which inhibit conversion of T3 to T4
2) Causes Hyopthyrodism (30%) or Hyperthyroidism (3%)
Amiodarone’s dermatological reactions?
1) Photosensitivity and rash are common
2) Longterm use can cause cyanotic or blue/gray pigmentation
Amiodarone’s Neurological Reactions?
1) Occur in about 40% of people
2) Includes peripheral neuropathy, muscle weakness, fatigue, tremors, ataxia, sleep disturbances, and headache
Amiodarone’s ocular effects?
Corneal microdeposits leading to optic neuropathic and or neuritis and visual impairment
Amiodarone Drug-Drug interactions?
1) ↓ Levels seen with CYP3A4 inducers
2) ↑Levels seen with CYP3A4 inhibitors
3) Amiodarone inhibits multiple CYP450 enzymes (i.e. CYP, 2C9, 2D6, 3A3, 3A4)
4) Inhibits the hepatic metabolism of Warfarin causing ↑ INR.
5) ↑ Levels of Digoxin by 50 to 100%
6) Amiodarone ↑ levels of Quinidine, Procainamide, Mexiletine, Cyclosporine, and Phenytoin
Amiodarone Dosing
1) VT/VF pulseless arrest ACLS algorithm - 300mg/20mL D5W or NS IV, then 2nd dose is 150mg
2) VT/VF maintenance - 1mg/min IV infusion x 6hrs, then 0.5mg/min x 18hrs (max of 2.2g in 24hrs)
3) For Tachycardia other than pulseless VT/VF - 150mg IV over 10mins, maintenance infusion = 1mg/min for 6hrs
Sotalol (Betapace) MOA
1) Non-selective Beta blocker (Class 2) and K+ channel blocker (Class 3)
2) K+ blockade seen at doses > 160mg
Sotalol (Betapace) Clinical Uses
1) Sustained V-tach
2) Maintenance of NSR in symptomatic A-fib and A-flutter
Sotalol (Betapace) characteristics
1) Only available PO
2) Supplied as a racemic mixture ( l-enantiomer more potent BB than d-enantiomer)
Sotalol (Betapace) Pharmacological effects?
1) Prolongs action potential (phase 3)
2) Prolongs APD and ERP and QT interval
3) ↓ Automaticity
4) Slows AV nodal conduction
5) Negative inotrope/chronotrope/dromotrope
Sotalol (Betapace) Pharmacokinetics
1) Low lipid solubility
2) Not protein bound
3) Not metabolized - excreted unchanged by kidney
4) Dosage adjustment required for patients with renal dysfunction
Sotalol (Betapace) Contraindications
1) Bronchial asthma
2) LV dystrophy, heart blocks in absence of pacemaker, ariogenic shock prolonged QT
Sotalol (Betapace) Adverse effects?
1) Torsades de Pointes (most dangerous and is dos
2) Hypotentsion, bradycardia, ↓contractility, fatigue and dyspnea
Ibultilide (Corvert) characteristics
1) Class 3 agent only available in IV form
2) K+ channel blocker
3) Delays repolarization by slow inward movement of Na+
Ibultilide (Corvert) Clinical Use
Conversion of recent onset A-fib or A-flutter to NSR
Ibultilide (Corvert) major warning
Ibultilide (Corvert) can cause potentially fatal arrythmias, particularly sustained polymorphic V-Tach with or without sustained QT prolongation.
Dofetilide (Tikosyn) Characteristics
1) A pure K+ channel blocker that is only available in PO form
2) Indicated for conversion of recent onset of a-fib and a-flutter to NSR
3) Hospital monitoring required for 1st 72 hours because of huge risk of TDP
4) Renal function and QTc must be monitored closely
5) DC TX if QTc increases > 15% or > 500msec
6) Correct hypokalemia, hypomagnesemia prior to initiation and maintain in normal ranges
Dofetilide (Tikosyn) Adverse effects
Headache, chest pain and dizziness
Dofetilide (Tikosyn) Drug-Drug interventions?
1) Increased risk of arrhythmias when combined with Halothane
2) Any agent that prolongs QT (i.e. phenothiazines, haloperidol, droperidol, dolasetron and zofran)
3) Any drug that inhibits renal secretion of dofetilide
4) CYP3A4 inhibitors (amiodarone, trimethoprim, and ketoconazole)
5) Hypokalemia and potassium depleting diuretics
Dronedarone (Multaq) Characteristics
1) Non-iodinated agent that is structurally related to Amiodarone
2) Officially classified as a Class 3 agent
3) Indicated to reduce the risk of hospitalization for a-fib in PTs already in SR
4) Only available in PO forms
Dronedarone (Multaq) MOA
Exhibits properties of all 4 classes of the Vaughn Williams classification (Class 1, 2, 3, 4)
Dronedarone (Multaq) metabolization
Extensively metabolized in the Liver via CYP3A4
Dronedarone (Multaq) most common adverse effect?
-Nausea and Vomiting
Dronedarone (Multaq) contraindications
1) Comitant use with Phenotizaine (i.e. compazine and prochlorperazine)
2) Any drug that prolongs QT
3) ↑ risk of death, stroke, and HF in PTs with decompensated HF or permanent A-fib
Adenosine MOA
1) An endogenous purine nucleoside with negative chronotropic and dromotropic effects
2) Binds Adenosine-1 receptors (G-protein coupled) in SA and AV nodes (resets SA and AV nodes)
Adenosine Clinical Use
1) Conversion to SR of Paroxysmal SVT including WPW syndrome
Adenosine Half-Life
t1/2 < 10 seconds - rapidly cleared from circulation via cellular uptake (hepatica and renal function does not alter its effectiveness or tolerability)
Adenosine dose
1) 1st Dose - 6mg IV push
2) 2nd dose - 12mg (3 mins apart)
- Max dose = 30 mg
Adenosine Adverse Effects
1) Flushing
2) SOB and chest burning and dyspnea
3) Headache and hypotension
4) Nausea
5) Complete AV blocks
Adenosine Drug interactions
- Methylxanthine derivatives (i.e. Theophylline and caffeine) are adenosine antagonists; and may require higher doses of adenosine effectiveness
- Dipyridamole (an adenosine) uptake inhibitor) potentiates or increases adenosine’s effect
Adenosine Contraindications
1) 2nd or 3rd degree block (except in PTs with pacemakers)
2) Sinus node disease (i.e. sick sinus syndrome, symptomatic bradycardia except in PTs with pacemakers)
Ivabradine (Corlanor)
1) Hyperpolarization-activated cyclic necleotide-gated (HCN) channel blocker
2) Anti-arrhythmic agent (new class approved in 2015)
Ivabradine (Corlanor) MOA
Slows diastolic depolarization by selectively and specifically inhibiting the Lf (funny current), which is responsible for regulating the intrinsic pacemaker activity in the SA node. This leads to a decrease in HR
Ivabradine (Corlanor) most common adverse effect
Bradycardia
