Far Eastern University- Nicanor Reyes Medical Foundation: Institute of Medicine

Course: PHARMACOLOGY
Topic: ANTI-ARRHYTHMITIC AGENTS [DOCUMENT TITLE]
00000000000000 - There is a plateau because at this point, the slow component of
CARDIAC ELECTROPHYSIOLOGY
the delayed rectifier K+ channels are partly open leaking out of
- Transmembrane potential is generated by an unequal distributions K+ (increased K+ conductance)
of charged ions between the intracellular and extracellular - Delicate balance between inward & outward current is
environment maintained during plateau
- Action potential requires an energy dependent process governed by - Net current is very small
three channels: Na, K, Calcium

A delicate balance between

ACTION POTENTIAL (NON-PACEMAKER CELL) inward and outward current is
maintained during this phase.
- Fast response action potential is the action potential coming from Net current is very small.
the non-pacemaker cells (ex., myocytes, atrium, ventricles)
- Remember the following:
 Na+ conductance refers to the inward movement of Na+ ions
 K+ conductance refers to the outward movement of K+ ions

INITIAL REPOLARIZATION PLATAEU PHASE

RAPID
REPOLARIZATION
PHASE 3: REPOLARIZATION
DEPOLARIZATION
- Ca++ channels are already closed and the K+ channels are open
- Increased K+ and decreased Ca++ conductance
RESTING POTENTIAL - Net movement of positive channels going out
- Returns the cell to resting membrane potential
- Due mainly to the delayed rectifier K+ channel which helps in final
PHASES OF ACTION POTENTIALS repolarization
PHASE 0: RAPID DEPOLARIZATION  Blocking these K+ channels will prolong the action
- It is rapid because it involves you Na+ channels which are rapidly potential
activated  opening THEN Na+ enters - Na+ channels are recovering from inactivation and preparing for
- The opening of Na+ channels is short-lived and soon be opening at phase 0
inactivated giving you a spike
- At this point, the K+ channels are closed
- Increased Na+ and decreased K+ conductance
- When a certain number of Na+ channels are inactivated, the cell
becomes refractory  cell becomes refractory to any form of
stimuli

PHASE 1: INITIAL REPOLARIZATION

- Slight decrease in action potential generated
- Na+ channels are inactivated  Lesser inward movement of
positive ions
- Transient outward current which is a K+ current, is open  K+ will
move outward
- Thus the cell will become less positive PHASE 4: RESTING POTENTIAL
- Decreased Na+ and increased K+ conductance - RMP: -90mV
- But since it is only transient, it will soon close - At this point the Ca++ and Na+ channels are closed, but the K+
channels are open
- Increased K+ and decreased Na+ and decreased Ca++
conductance
- But if the K+ ions are continuously moving out, you will expect the
action potential to be more negative, this will not happen because
there will be an inward leak of Na+ ions

Abnormalities in phase 1 is correlated to a genetic disease called the

Brugada syndrome where in the patient develops sudden ventricular
tachycardia leading to fibrillation and eventually death.
RMP is governed by:
K+ channels open
Ca++ and Na+ channels closed
PHASE 2: PLATEAU PHASE
- Opening of slow Ca+ channels (once they open, they close slowly) Depolarized state:
- Increased Ca+ conductance greater movement of positive ions K+ channels close
inside the cell Na+ and Ca++ channels open

[DOCUMEN
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SOURCES: Angel Trans, Pharmacology Lab Manual, Katzung, 2018 Doc Reyes lecture
 Far Eastern University- Nicanor Reyes Medical Foundation: Institute of Medicine
Course: PHARMACOLOGY
Topic: ANTI-ARRHYTHMITIC AGENTS [DOCUMENT TITLE]
00000000000000
ROLE OF IK1 IN THE CARDIAC ACTION POTENTIAL
- IK1  Inward Rectifier current Automaticity
- Keep resting membrane potential close to equilibrium - It the cell’s ability to spontaneously raise the membrane potential
- Marked reduction of this outward current is responsible for the above the threshold in order to rapidly initiate the AP
prolonged action potential duration (APD)
- Helps in repolarization
VENTRICULAR RESPONSE AND THE ECG
SUMMARY  PR interval reflects AV node conduction
PHASE Na+ K+ Ca+ - If AV node conduction is slower prolonged PR interval
0 RAPID DEPO   -  QRS complex corresponds to phase 1
1 INITIAL REPO   - - Duration reflects the conduction in the ventricles which is
2 PLATEAU - -  carried out by the His-Purkinje system
3 REPO -   - If blocked ventricular conduction: longer QRS complex
4 RESTING POTENTIAL     QT interval measures the duration of action potential
- K+ channel blockade  prolong action potential 
ACTION POTENTIAL (PACEMAKER CELL) prolonged QT interval

- Sodium does not participate in the initiation of action potential and

REFRACTORY PERIODS
could only offer background currents (funny currents)
 REFRACTORY PERIOD
- Cardiac cells are transiently unresponsive to any stimuli
 ABSOLUTE REFRACTORY PERIOD (ARP)
- Begins at the onset of AP and ends at the cell response
of local non-conductive stimuli
- Starts at phase 0
- Incorporated within the ERP and probably ends at the
RRP
 EFFECTIVE REFRACTORY PERIOD (ERP)
- Begins at depolarization
- Will not respond to any stimuli of any magnitude
- Begins at phase 0
 RELATIVE REFRACTORY PERIOD (RRP)
- Begins at the end of ERP
- Stimuli will provoke a response if greater than the
threshold
- Usually begins at phase 3
- May develop early depolarization

ARRHYTHMIAS
SUMMARY
PHASE ACTION MECHANISMS OF ARRHYTHMIAS
0 DEPO  Ca2+  K+ Primarily caused by abnormal pacemaker activity or abnormal
3 REPO  Ca2+  K+ impulse propagation. Therefore, the aim of therapy of the
4 SPONTANEOUS DEPO  Ca2+  K+ arrhythmias are the ff:
 Reduce ectopic pacemaker activity
 Modify conduction or refractoriness in reentry circuits
PHASES OF ACTION POTENTIALS to disable circus movement.
PHASE 0: DEPOLARIZATION - Arrhythmias result from disturbances in impulse:
- Na++ does not participate in the initiation  Generation
- Ca++ channels will open  Conduction
 Remember that these are slow channels, this is
why there is a slow gradual rise in the AP and no BRADYARRHYTHMIAS
spike is seen
- K+ channels are closed - Slow and irregular  Pacemaker
- Increased Ca++ and decreased K+ conductance - Causes:
PHASE 3: REPOLARIZATION  Failure of impulse generation within SA node
- Ca++ channels are closed and K+ channels are open  Failure of excitatory wave front to conduct from the
- Increased K+ and decreased Ca++ conductance atrium to the ventricle through AV node
- Returning the cell to its spontaneous depolarization phase - Not amenable to long-term pharmacologic therapy and may
(equivalent to RMP in non-pacemaker cells) require permanent cardiac pacing (patient needs a pacemaker)

PHASE 4: SPONTANEOUS DEPOLARIZATION TACHYARRHYTHMIAS

- “Funny” currents (If) through slow Na+ channels and starts
- Fast and Irregular
to leak which is necessary among automatic cells
- Causes:
- Notice that the RMP is less negative (-60mV)
 Abnormal automaticity
- Increased Ca++ and decreased K+ conductance
 Triggered activity
[DOCUMEN
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SOURCES: Angel Trans, Pharmacology Lab Manual, Katzung, 2018 Doc Reyes lecture
 Far Eastern University- Nicanor Reyes Medical Foundation: Institute of Medicine
Course: PHARMACOLOGY
Topic: ANTI-ARRHYTHMITIC AGENTS [DOCUMENT TITLE]

 00000000000000
Reentry - Due to increased intracellular ionized Ca++  activates inward
- May be palliated with long-term medical therapy ionic current  movement of Na+ or K+
- Causes:
ABNORMAL AUTOMATICITY  Hypokalemia, hypercalcemia
 Rapid HR
- Due to increased phase 4 slope  cell is less negative at RMP 
 Myocardial ischemia
can easily fire impulses
 Cell is in its depolarized cell  increased calcium
- May occur in cells that normally display spontaneous diastolic
inside the cell
depolarization: the sinus and AV nodes and the His-Purkinje
system  Adrenergic stress, digitalis glycosides, catecholamines
- May result from:  Increase entry of calcium into the cell
- Respond to:
 Activation of β-adrenoreceptors
 β adrenoreceptors are Gs proteins/metaboreceptors  L-type calcium channel antagonists
a. Activation will lead to increase cAMP in the  B-adrenoceptor antagonists – to avoid adrenergic stress
heart
b. Activation of phosphokinase A  opening of DRUGS BLOCK THE DADS OR EADS
Ca++ cannels in the myocardium - Inhibition of the development of the after depolarizations
c. Ca++ stimulate RYR2 in the sarcoplasmic - Interference with the inward current (Na or Ca channels)
reticulum
d. Ca++ moves out  increase Ca++ in the REENTRY/REACTIVATION MODEL
cytoplasm
- Also known as “circus movement”, in which one impulse reenters
e. Increase contractility
and excites areas of the heart more than once (Katzung)
 Hypokalemia
- Can take place within:
 K+ may be inside the cell
 A small local region within the heart
 Stretching of cardiac cells
 It can occur, for example, between atria and ventricles
 Positive chronotropic drugs
(global reentry)
 Acidosis & partial depolarization by currents of injury
- Clinical Examples:
 Cause injury to the heart and may cause injury and
 Wolff-Parkinson-White Syndrome: AV reentrant
ischemia which are always depolarized
tachycardia
DRUGS MAY SLOW AUTOMATIC RHYTHMS BY ALTERING ANY OF THE  Atrial or ventricular tachycardia: AV nodal tachycardia,
atrial flutter
DETERMINANTS OF SPONTANEOUS PACEMAKER DISCHARGE
- For reentry to occur, certain conditions must be met that are
 Decrease phase 4 slope
related to the following:
 Give beta blockers
 There must be an obstacle (anatomic or physiologic) to
 Increase threshold potential
homogenous conduction
 Give Na channel, calcium channel blockers
 Establishing a circuit around which the reentrant
 Increase maximum diastolic potential
wavefront can propagate
 Give adenosine
 The presence of a unidirectional block within a conducting
 Increase action potential duration
pathway
 Prolongs the ERP  thus cell will not be amenable
to any stimulus  Conduction must die out in one direction but
continue in the opposite direction
 Give potassium channel blocker
 The length of the effective refractory period of the normal
tissue
AFTER DEPOLARIZATIONS (AD) OR TRIGGERED ACTIVITY
 Conduction time around the circuit must be long
A. EARLY (EAD, TORSADES DE POINTES) enough that the retrograde impulse does not enter
- Can occur during the relative refractory period refractory tissue as it travels around the obstacle
- Due to decreased outward K+ currents - To prevent reentry
- Causes:  Prolong the ERP so that it will not be stimulated
 Hypokalemia, hypoxia, acidosis  Increase the threshold of action potential by:
 Causes ischemia in the heart which causes K+ to  Reduce the rise of phase 0: give Na+ channel
accumulate inside the cell blockers
 Sotalol, quinidine
 Known as potassium channel blockers
 β-adrenoceptor, dofetilide, ibutilide, amiodarone
(rare)
- Effectively terminated by:
 Procainamide
 Potentially prolong AP (not as greater as quinidine)
 A class IA anti-arrhythmic
 Lidocane
 1st choice
 Shortens AP
 Class IB anti-arrhythmic

B. LATE OR DELAYED (DAD)

- Occur during the resting membrane potential
[DOCUMEN
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SOURCES: Angel Trans, Pharmacology Lab Manual, Katzung, 2018 Doc Reyes lecture
 Far Eastern University- Nicanor Reyes Medical Foundation: Institute of Medicine
Course: PHARMACOLOGY
Topic: ANTI-ARRHYTHMITIC AGENTS [DOCUMENT TITLE]
00000000000000 Slow delayed rectifier K+ channel (IKS), inward rectifier,
ANTI-ARRHYTHMIC AGENTS
transient outward current, L-type Ca++ current.
- Actions: - Pharmacologic Actions
 Directly alter the function of ion channels that participate in  Anticholinergic effects
a normal heartbeat (except class II)  Alpha adrenergic blockade – β receptors will predominate 
 Interfere with neuronal control vasodilation
 Local anesthetic properties (decreased excitability)
VAUGHAN-WILLIAMS CLASSIFICATION ANTI-ARRHYTHMICS  Prolongs repolarization in Purkinje fibers and ventricular
muscles
- Oldest and the only classification for anti-arrhythmic agents  Prolongs QRS complex and QT interval
 QRS complex is prolonged due to slow ventricular
Class Basic mechanisms Actions conduction because with high concentration it can also
I Sodium-channel Effects on kinetics of Na channel inhibit Ca++ channels
blockade blockade and APD (action Toxic effects: QT interval prolongation, Torsades de pointes
potential duration) arrhythmia, Slowed conduction THROUGHOUT the heart
II Sympatholytic Reduce cardiac beta- adrenergic (excessive Na channel blockade)
activity
III Prolongation of action Block the rapid component of 2. PROCAINAMIDE
potential the IKr By blocking Na+ channels
IV Blockade of cardiac Slows conduction in the SA  Slows conduction
calcium current  Prolongs the QRS duration of ECG
Nonspecific blockade of K+ channels  Prolongs APD
- Additional mechanisms
CLASS 1 ANTI-ARRHYTHMITICS
 Increased threshold for excitation in atrium and ventricles
- Basic mechanism: Na-channel blockade  Slowing Phase 4 depolarization  decreased abnormal
- Action: reduce phase 0 slope and peak of action potential automaticity
- Key element is the dissociation rate  Non-specific blockade of K+ channels  prolong APD
 Prolong QRS complex
Class Basic mechanisms Actions - Other Pharmacological Factors
IA Moderate Na- Moderate reduction in phase 0  Direct depressant action on the SA and AV nodes
channel blockade slope;  Ganglion blocking properties
Increase APD; Parasympathetic effects predominate decreased
Increase ERP BP
Has Na+ and K+ channel blocking Reduces PVR and may cause hypotension (Less
effect prominent effects than Quinidine)
IB Weak Na-channel Small reduction in phase 0 slope; HYPOTENSION  rapid procainamide infusion +
blockade Reduce APD; Severe LVD
-fast dissociation rate Decrease ERP  Anticholinergic effects (lesser than quinidine)
Does not interfere with K+ channels
IC Strong Na-channel Pronounced reduction in phase 0 3. DISOPYRAMIDE
blockade - Among the three, this is not the first line agent
-slow dissociation rate - Suppresses atrial and ventricular arrhythmias
- Increased refractory period in His-Purkinje and ventricular muscle
Sodium-Channel Blockade Approved only for the treatment of Ventricular arrhythmias
IC > IA > IB - Additional Pharmacological Effects
 Negative inotropic effect
Increasing in the ERP  Anticholinergic effects (prominent or greatest)
IA > IC > IB (decreases)  Has atropine like activity
- Influenced by K+ concentration
Duration of K+ repolarization  Hypokalemia  lesser effects
current  Hyperkalemia  greater effects
IA > IB
IC – no effect PHARMACOKINETIC PROPERTIES (CLASS IA)
KINETICS QUINIDINE PROCAINAMIDE DISOPYRAMIDE
Oral >80% 75-85% 87-95%
bioavailability
NAPA >80%
DRUGS OF CLASS IA Onset of 1-3hrs 5-10min 30min-3.5hrs
action
1. QUINIDINE Peak 1-2hrs 60-90min 30min-3hrs
- Mechanism of Action response
 Blockade of Na+ channels Duration of 6-8hrs 4-10hrs 1.5-8.5hrs
Slows the upstroke of AP action
Half-life 4-10hrs 3-4hrs 4-10hrs
Slows conduction
Prolongs QRS duration NAPA: 6-10hrs
Primary route Liver Liver Liver
 Inhibits rapid delayed rectifier K+ channel (IKR) of
 High concentration: metabolism
Active Active
metabolite metabolite
[DOCUMEN
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SOURCES: Angel Trans, Pharmacology Lab Manual, Katzung, 2018 Doc Reyes lecture
 Far Eastern University- Nicanor Reyes Medical Foundation: Institute of Medicine
Course: PHARMACOLOGY
Topic: ANTI-ARRHYTHMITIC AGENTS [DOCUMENT TITLE]
00000000000000 Active DRUG INTERACTIONS (CLASS IA)
metabolite  Increase plasma concentration of:
(NAPA)  Codeine
Primary route 10-50% 5-60% 80% renal  Flecainide
of excretion
Renal Renal (50%  Propafenone
(unchanged) (unchanged) unchanged)  Reduces clearance of:
Therapeutic 2-5ug/mL 4-8ug/mL 1-5 ug/mL  Digoxin
serum
concentration
NAPA: 10 to  Plasma concentration decreased by:
20ug/mL  Phenobarbital
- Chronic among the three is Procainamide  Phenytoin
 Procainamide gives rise to a metabolite called NAPA (N-  Rifampicin
acetyl procainamide) which is active o These are known enzyme inducers which will
 If the concentration of NAPA >5ng/mL  can possess increase the metabolism of class IA drugs 
class III activity (K-blocking effect)  it can reduce decreased toxic effects
outward movement of K  Plasma concentration increased by:
 Cimetidine
 If the concentration of NAPA is >20ng/mL 
torsades de pointes  Verapamil
 Observed only in patients with renal failure o These are known enzyme inhibitors which will
due to decreased clearance decrease the metabolism of class IA drugs
increase toxic effects
 Formation of NAPA depends upon acetylation
 We are fast acetylators  greater NAPA
production DRUGS OF CLASS IB
- No anti-cholinergic effects
CLINICAL USE (CLASS IA) - Allows recovery from blockade in between action potentials because
 Atrial fibrillation, flutter it has a fast dissociation with Na-channel blocking effect
 Supraventricular tachyarrhythmias
 By reducing phase 0 1. LIDOCAINE
 Ventricular tachyarrhythmias - Used for defect of enhanced automaticity
 By reducing phase 0 - Greater effects on Purkinje and ventricular cells
 Disopyramide is only approved for the treatment of - Pharmacologic Actions:
ventricular arrhythmias  Blocks both inactivated and activated Na+ channels
 Wolff-Parkinson White Syndrome (WPW)  Reduces slope of Phase 4
 Premature ventricular contractions  Increased conduction velocity
 Increased ventricular fibrillation threshold
COMMON ADVERSE EFFECTS (CLASS IA) - DOC for patients of ventricular arrhythmias associated with MI
 QT interval prolongation  In ischemic patients or patients with MI, tissues are always
 Due to prolonged action potential caused by K+ channel depolarized or is rapidly driven and it is said that Na-
blocking effect channel blockade is longer
 Torsades de Pointes or EAD  If you give drugs with a short blocking effect, the effect is
 Due to decreased K+ outward movement longer because the tissues prolong the Na-channel
blockade
QUINIDINE PROCAINAMIDE DISOPYRAMIDE  This is why lidocaine or is preferred because since it has
- Black water fever - Anticholinergic - Anticholinergic short acting effect, even if it will prolong because of the
- Anticholinergic (weak) (strong) ischemic tissue it will not be too toxic compared with
(moderate) - Relative short half- - Negative drugs with long acting effects like class IC
- Cinchonism life inotropic effect  2nd drug of choice is Procainamide
(blurred vision, - Lupus-like - Atropine-like - Not given orally because of first pass metabolism
tinnitus, headache, syndrome (25-30%): activity
psychosis) o Rash, joint and muscle Urinary
- Vagolytic effects pain, pericarditis 2. PHENYTOIN
retention in
(hypotension, pro- o Not an indication to male px with
- More on anticonvulsants
arrhythmia) stop treatment
prostatic - Rapid
- Enhances digitalis - Syncope hyperplasia - Depresses membrane responsiveness in the ventricular
toxicity - Hypotension Precipitates myocardium, His-purkinje system and atrium
- GI upset (diarrhea, - Nausea, diarrhea glaucoma - Additional Pharmacologic Actions:
(10%)
nausea, vomiting, - CHF; pro-  Increased sympathetic tone
- Fever
abdominal cramping) arrhythmia  Decreased PR and QT intervals
- Thrombocytopenia - Hepatitis (<5%)
- Hepatitis - Agranulocytosis
(0.2%)
3. MEXILETINE
- Angioneurotic - Orally active congener of lidocaine
- Cardiac and GI
edema - Pharmacologic Actions:
toxicity (Noted if
- Fever (Rare) procainamide is >8ng/mL  Exerts a negligible effect on repolarization
and if NAPA is >20ng/mL)  Blocks Na+ channels with rapid kinetics
 Relieve chronic pain (diabetic neuropathy and nerve
injury)  given orally

[DOCUMEN
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SOURCES: Angel Trans, Pharmacology Lab Manual, Katzung, 2018 Doc Reyes lecture
 Far Eastern University- Nicanor Reyes Medical Foundation: Institute of Medicine
Course: PHARMACOLOGY
Topic: ANTI-ARRHYTHMITIC AGENTS [DOCUMENT TITLE]
00000000000000
CLINICAL EFFICACY & PHARMACOKINETIC PROPERTIES (CLASS IB) dysarthria, altered level of
KINETICS LIDOCAINE MEXELETINE TOCAINIDE consciousness, seizures,
Oral paresthesia
30-40% 90-100% Approx. 100%
bioavailability - Nystagmus
Onset of 5-15 mins IM 0.5-2 hours Not known PHENYTOIN TOCAINIDE
action Immediate IV CNS effects Pulmonary fibrosis
Peak Unknown 2-3 hours 0.5-2 hours Allergy
response
Duration of 60-90 mins 8-12 hours 8 hours
action IM; DRUGS OF CLASS IC
10-20 mins IV
Half-life
1. FLECAINIDE
Initial: 8 mins 9-15 hours 15 hours
- Slows down conduction on all parts of the heart
Terminal: 120
- Potent blocker of Na and IKr channels with slow unblocking
mins
kinetics
Steady state 8-10 hours
concentration - Open channel blocker of RyR2 Ca++ release channels
Primary route 90% liver Liver Liver - Prolong PR, QRS, QT interval
of - Additional Pharmacological actions:
metabolism  Local anesthetic
Primary route 10% renal Primary Renal (40%
of excretion (unchanged) biliary; unchanged) 2. PROPAFENONE
remainder 10% renal - Low potent L-calcium channel blocker
metabolites - Weak β-adrenergic receptor blocking activity
Clinical IV only Good efficacy Digitalis- - Range of activity similar to quinidine
efficacy VT and PVCs in ischemic induced - Structural similar to propanolol
Good efficacy myocardium arrhythmias - No effect on AP duration
in ischemic
myocardium 3. MORICIZINE
 LIDOCAINE - Withdrawn in the US
- Given parenterally because of a great first pass effect - Phenothiazine derivative
- Very short half-life and steady state is hard to achieve fast, this - No AP Prolongation
is why you have to give a loading dose - Potent Na++ channel blocker
 Loading dose is given at 150-200mg over 15 mins
 Maintenance dose is given at 2-4mg per min CLINICAL USE OF CLASS IC
- When your patient has heart failure, the volume of distribution - Common indications
decreases decrease clearance, lower the maintenance and  Life threatening supraventricular tachyarrhythmias (SVT)
loading dose  Ventricular tachyarrhythmias (VT)
- When the patient has hepatic failure  decrease clearance, FLECAINIDE PROPAFENONE MORICIZINE
lower the maintenance dose only - Supraventricular - SVT - VT
 Cimetidine and propranolol decreases hepatic blood tachycardia - Paroxysmal AF and - IB Activity
flow - Paroxysmal SVT VT
 MEXILETINE - Catecholaminergic - WPW
- Can be given orally because it has no first pass effect polymorphic (CP),
- Half-life shortens by 35% with smoking (enzyme inducer) - VT

CLINICAL USE (CLASS IB) Side effects are greater

when given to patients
 Ventricular tachyarrhythmias (VT) with existing ventricular
 Prevention of ventricular fibrillation after cardioversion tachyarrhytmia or MI
(prophylaxis)
 Premature ventricular contractions
 Chronic Pain (e.g. DM neuropathy) PHARMACOKINETIC PROPERTIES
 DOC: MEXILETINE KINETICS FLECAINIDE PROPAFENONE MORICIZINE
Oral 85-90% Nearly complete Not known
bioavailability
ADVERSE EFFECTS (CLASS IB) Onset of 1-2 hours 1 hour Within 2 hours
LIDOCAINE MEXILETINE action
- Least cardiotoxic because - Adverse effects are Peak 1.5-6hours 2-3 hours 6 hours
response
of its rapid dissociation minimized by giving food
Duration of 1-2 days 8-12 hours 10-24 hours
kinetics - Dose Related Side Effects: action
- Proarrhythmic effects - Neurologic Half-life 10-18 hours 2-32 hours 1.5-3.5 hours
(uncommon)  Drowsiness, tremor, Primary route Liver CYP2D6 Liver CYP2D6 Liver
- Hypotension (with muscle twitching blurred of
vision, lethargy, seizures, metabolism
preexisting HPN, large
paresthesia Primary route 10-50% renal 18.5-38% 56%
doses) of excretion
- Neurologic – main adverse - Nausea, vomiting, 5% fecal renal biliary/fecal
effect diarrhea (unchanged) 39% renal
Therapeutic 0.2-1.0 ug/ml <1 ug/ml Not
 Dizziness, drowsiness, serum
muscle twitching, tremor, concentration
established
[DOCUMEN
RAPL2019
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SOURCES: Angel Trans, Pharmacology Lab Manual, Katzung, 2018 Doc Reyes lecture
 Far Eastern University- Nicanor Reyes Medical Foundation: Institute of Medicine
Course: PHARMACOLOGY
Topic: ANTI-ARRHYTHMITIC AGENTS [DOCUMENT TITLE]

ADVERSE EFFECTS 00000000000000  Decreased AV node conduction velocity (block ISA –

FLECAINIDE PROPAFENONE MORICIZINE intrinsic sympathetic activity)
- Life-threatening VT, - Metallic taste and - Dizziness, nausea,
negative inotropic constipation peripheral DRUG HTN ANGINA ARRHY MI CHF
effect, - Beta blocking and numbness, NON-SELECTIVE BETA BLOCKERS
proarrhythmogenic, calcium channel euphoria CARTEOLOL X
- CNS side effects blocking activity - Exacerbate CARVEDIOL X X
(dizziness, tremor, can worsen heart arrhythmia LABETALOL X X
light headedness) failure NADOLOL X X X X
- Flushing, blurred - Exacerbation PENBUTOLOL X X
vision, metallic taste arrhythmias PINDOLOL X X
- CNS effects PROPRANOLOL X X X X
- Worsening of SOTALOL X
asthma TIMOLOL X X X X
- Blurred vision
B1 SELECTIVE BETA BLOCKERS
ACEBUTOLOL X X X
ATENOLOL X X X X
BETAXOLOL X X X
BISOPROLOL X X X
ESMOLOL X X
METOPROLOL X X X X X
REMEMBER!!!
HTN  All
ANGINA  All EXCEPT “CAR-CAR-SO”
ARRHY  All EXCEPT “PEN, PIN, CAR2, LA-SO”
MI  “PRO MET ATE NAD.”
CHF  “TIM CARVE MET”
- Rates of recovery from drug-induced block (τ recovery) under
physiologic conditions (Goodman & Gilman)
PHARMACOKINETIC PROPERTIES
- T-recovery is the time required to complete approximately 63% of
KINETICS PROPANOLOL ESMOLOL ACEBUTOLOL
an exponentially determined process which is the Na-channel
Oral 30-40% N/A 70%
blockade bioavailability
- If the T-recovery is <1 second, the block is very rapid Onset of 1-2 hours 2-5min 1-3 hours
o Can only be prolonged in cases where in the tissues are action
Peak 1-15 hours 15-30 min 3-8 hours
ischemic
response
- If the T-recovery is ≥10 seconds, the same number of Na++ channels Duration of 6-24 hours 20-30 mins 12-24 hours
will be blocked in diastole and systole  prolonged PR interval action
Half-life 3-5 hours 5-10 mins 3-4 hours
Primary route Liver Liver Liver
CLASS 2 ANTI-ARRHYTHMITICS (BETA BLOCKERS) of
metabolism
- Basic mechanisms of anti-arrhythmics Primary route Renal Renal Renal
 Block sympathetic activity of excretion (30- 40%)
 Reduce rate and conduction Biliary/Fecal
- Major actions of class II (50-60%)
 Blockade of myocardial β1-adrenergic receptors Therapeutic 0.02 – 1 uq/mL 0.4-1.2 ug/mL Not established
 Direct membrane-stabilizing effects at higher concentrations serum
concentration
related to blockade of Na channels
- Beta 1 blocker is more preferred for arrhythmias
- Cardiac Effects
- Esmolol has no ISA
 Decrease contractility
 Decreased relaxation rate ADVERSE EFFECTS
 Decrease heart rate  Negative chronotropic and inotropic effects
 Decrease conduction velocity  Bradycardia
- Vascular effects  Precipitates CHF
 Smooth muscle contraction (mild vasoconstriction)  Decreasing firing of SA node  decrease heart rate 
 Increased cAMP will stimulate the cytosolic calcium to lesser pumping action of the heart  lesser ejection
go inside the sarcoplasmic reticulum  vasodilation fraction  decrease CO
 Not given in patients with acute CHF
DRUGS OF CLASS 2  AV conduction block
1. PROPANOLOL
- Site of action:
CLASS 3 ANTI-ARRHYTHMITICS (K+ CHANNEL BLOCKERS)
 Atrium, ventricle
 His-Purkinje system - Basic Mechanism: Delay repolarization (phase 3) and thereby
- Pharmacologic Actions – SA>AV node increase action potential duration and effective refractory period
 Slowing of SA node and ectopic pacemaker automaticity DRUGS OF CLASS III
(greater effect) 1. AMIODARONE
[DOCUMEN
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SOURCES: Angel Trans, Pharmacology Lab Manual, Katzung, 2018 Doc Reyes lecture
 Far Eastern University- Nicanor Reyes Medical Foundation: Institute of Medicine
Course: PHARMACOLOGY
Topic: ANTI-ARRHYTHMITIC AGENTS [DOCUMENT TITLE]

- 00000000000000
Poor absorption, but once absorbed the heart tissue to plasma  Affected and dependent to extracellular K+
concentration is 20:1 (50x more in the heart) concentration
- Effects may last for 1-3 months and may be measured for up to 1  Hypokalemia  exaggerated response
year from the time of discontinuation  Hyperkalemia  lesser response
- Iodine rich drug  Decrease effects in MI patients
- Actions  QT-interval prolongation
 Class I, II, III, and IV and therefore decreases phase 4 slow Effects are directly related to plasma
and conduction velocity concentration; thus dosage is based on px’s Crea
 Blocked inactivated Na+ and Ca++ channels clearance
(class I and IV) - Therapeutic Uses
 Non-competitive beta-blocker (class II)  Supraventricular arrhythmias
 Predominant K-blocking effect (this is why it is  Atrial flutter and fibrillation conversion and prophylaxis
labelled as class III) Maintenance / restoration of normal sinus rhythm in
 Prolongs PR, QRS, and QT interval patients with atrial fibrillation
 Peripheral vasodilatation - Drug Interaction
- Therapeutic Uses Verapamil increases Peak plasma dofetilide concentration
 Atrial Fibrillation by increasing intestinal blood flow
 Paroxysmal atrial fibrillation
 Severe supraventricular and ventricular arrhythmias 6. IBUTILIDE
 Acute and recurrent ventricular tachycardia or fibrillation - Actions
resistant to other drugs  Slow inward Na+ activator, which delays repolarization (AP
prolongation)
2. DRONEDARONE Blockade of the rapid component (Ikr) of the delayed
- Structural analogue of amiodarone but has no iodine content rectifier potassium current (Slows depolarization)
 Iodine is replaced by methane sulfhydryl group on the  Extensive first pass effect
benzofuran ring - Therapeutic Uses
 Has shorter half-life but eliminates the thyroid effect  Supraventricular arrhythmias
- Actions  Acute conversion of atrial flutter and fibrillation to normal
 Class I, II, III and IV sinus rhythm (Effectivity: Flutter> fibrillation)
 Prolong QT interval - Adverse Effects
- Therapeutic Uses Excessive QT prolongation
 Atrial Fibrillation Torsades de pointes
 Atrial Flutter
- Not given in patients with severe heart failure PHARMACOKINETIC PROPERTIES
KINETICS AMIODARONE DRONADERONE
3. BRETYLIUM Oral 30% <20% (15%)
bioavailability
- Actions
Onset of 2-3 days, up to 2-3 months
 Prolongs AP action
 Interferes with reuptake of NE Peak 3-7 hours (IV) 3.5 hours (3 to 6
- Therapeutic Uses response
hrs)
 Treats and prevents recurrence of ventricular fibrillation Duration of Variable, weeks to months
action
Half-life 2-10 days; 13 to 19 hours
4. SOTALOL
- Actions 26-107 days with
 L-isomer has Class 2 activity (Beta-adrenergic blocking chronic
action  non-selective) in low doses administration
Primary route Liver CYP3A4 active Liver
D- and L- isomers share action potential prolonging actions of
 Exists at D and L isomer at conventional or therapeutic metabolism
metabolites (N-desethyl- N-debutylation to
amiodarone) form active N-
doses – Class 3 activity
 Prolong QT interval debutyl metabolite
Primary route Biliary, negligible in Feces (84%)
 Decrease automaticity, slow AV node conduction, prolong of excretion
AV refractoriness Urine Urine (6%)
Therapeutic 0.5-2ug/mL
Decreases the threshold for cardiac defibrillation serum
- Therapeutic Uses concentration
 Life-threatening ventricular arrhythmias
 Maintenance of sinus rhythm with atrial flutter and
fibrillation KINETICS SOTALOL DOFETILIDE IBUTILIDE
 Supraventricular and ventricular arrhythmias in the Oral >80% >80% <5%
bioavailability 100% oral
pediatric age group
Onset of 0.5 hour 0.5 hour Rapid
action
5. DOFETILIDE Peak 1-2 hours 23 hours 20 min
- Actions response
 Very selective K+ channel blocker Duration of 12-24 hours 8-10 hours
action
 Selective to the rapid component of the delayed Half-life 8 hours 7-10 hours 6 hours
rectifier K+ channels
(range 2-12
[DOCUMEN
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SOURCES: Angel Trans, Pharmacology Lab Manual, Katzung, 2018 Doc Reyes lecture
 Far Eastern University- Nicanor Reyes Medical Foundation: Institute of Medicine
Course: PHARMACOLOGY
Topic: ANTI-ARRHYTHMITIC AGENTS [DOCUMENT TITLE]
00000000000000 hours)  Azole antifungals – inhibits metabolism
Primary route Liver (80%) Liver Liver  Protease inhibitors – promotes metabolism
of
metabolism
(CYP3A4)
CONTRAINDICATION
Primary route Renal (20% Renal (80% Renal
of excretion  Dronedarone
unchanged) unchanged; - Class IV heart failure during pregnancy (Category X)
40% 20%
metabolite metabolites)  Dofetilide:
Therapeutic 1-4 ug/mL Not N/A
serum - Baseline QTc of > 450 ms in the presence of conduction delay
concentration
established - Bradycardia of < 50 bpm, hypokalemia
- Ibutilide has the highest first pass effect and is given via IV
CLASS 4 ANTI-ARRHYTHMITICS (Ca2+ CHANNEL BLOCKERS)
ADVERSE EFFECTS
 Amiodarone - Mainly your non-DHPs which has cardiac and vascular suppressant
May produce symptomatic bradycardia and heart block in effects
patients with preexisting sinus or AV node disease  Examples: verapamil, diltiazem
- CVS: hypotension, bradycardia, precipitates CHF - More effective on spontaneously firing cells or tissues
- Pulmonary: dose-related toxicity (pulmonary fibrosis, - Basic mechanisms
pneumonitis)  Block L-type calcium-channels  decreased intracellular
- Thyroid abnormalities calcium
Blocks the peripheral conversion of thyroxine (T 4) to  Most effective at SA and AV nodes
triiodothyronine (T 3). It is also a potential source of large  Reduce rate and conduction
amounts of inorganic iodine. - Actions
 Depends on the iodine concentration in the body  Cardiac effects
 Low iodine stores  Decrease contractility
 Jod-Basedow phenomenon  Decrease heart rate
 Hyperthyroidism  Decrease conduction velocity
 High or normal iodine stores  Vascular effects
 There are excess amounts of thyroid  receptors  Smooth muscle relaxation (vasodilatation)
become saturated  Wolff-Chaikoff effect  Suppress both early and delayed after depolarizations
 Hypothyroidism  Peripheral vasodilatation
- Abnormal liver function test (hypersensitivity hepatitis) - Site of Action
- Skin: Photosensitivity, gray-blue discoloration in sun-exposed  SA < AV nodes
areas
- Eyes: Blurred vision, asymptomatic corneal microdeposits, KINETICS DILTIAZEM VERAPAMIL
photophobia, optic neuritis Oral Not measured 20%
bioavailability
- CNS: Ataxia Onset of 10 secs (IV) 1-2 hours
action
 Dronedarone Peak Not measured 1-2 hours
- CVS: bradycardia, increase risk of death stroke, heart failure response
Duration of 10-20 secs 8-10 hours
- Pulmonary: no toxicity action
- Thyroid: No toxicity Half-life 4 hours 3-7 hours
- Liver toxicity Primary route Red blood cells Liver
- Nausea, vomiting, diarrhea, abdominal pain, asthenia: of
Active metabolite
prominent metabolism
Primary route Renal, inactive Renal (30% unchanged)
- Dermatitis or Rash of excretion
Metabolite
Therapeutic Not applicable 0.125 – 0.4 ug/ml
 Dofetilide, ibutilide serum
- Headache concentration
- Proarrhythmia (torsades de pointes – occurs at high doses/dose
dependent) ADVERSE EFFECTS
- Chest pain - Hypotension (Vasodilatation)
- Dizziness In the setting where administration of IV Verapamil is
- Nausea done to a patient with ventricular tachycardia
misdiagnosed with supraventricular tachycardia.
 Sotalol - Negative inotropic and chronotropic effects  bradyarrhythmias
- Fatigue - AV block (large doses or px with AV nodal disease)
- Dizziness  Give Atropine/Beta Agonists to reverse
- Dyspnea - Constipation
- Modest negative inotropic and chronotropic effects - Lassitude
(bradycardia), proarrhythmia (torsades de pointes – 1.5 to 2%) - Nervousness
- Peripheral Edema: due to sodium and water retention
DRUG INTERACTION
- With amiodarone: increase concentration of digoxin, statins, THERAPEUTIC USE
warfarin - Supraventricular tachycardia
- Altered metabolism of dronedarone by: Major arrhythmia indication for Verapamil
[DOCUMEN
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SOURCES: Angel Trans, Pharmacology Lab Manual, Katzung, 2018 Doc Reyes lecture
 Far Eastern University- Nicanor Reyes Medical Foundation: Institute of Medicine
Course: PHARMACOLOGY
Topic: ANTI-ARRHYTHMITIC AGENTS [DOCUMENT TITLE]

- 00000000000000
Atrial fibrillation and flutter - Activation of inward rectifier K currents and inhibition of
By reducing ventricular rate; rarely converts atrial calcium current
F&F to sinus rhythm - Decreases the slope of phase 4 of the pacemaker action
- Ventricular arrhythmias potential decreasing its spontaneous firing rate (negative
- Hypertension chronotropy)
- Peripheral vasospastic disorder - Inhibits conduction velocity (negative dromotropic effect)
and increases refractory period particularly at the
atrioventricular (AV) nodes

PHARMACOKINETIC PROPERTIES
- Half-life (in human blood = less than 10 secs)
- Route of administration: bolus intravenous injection or as
an intravenous infusion

INDICATIONS
- DOC conversion of paroxysmal SVT to sinus rhythm

ADVERSE EFFECTS
- Flushing (20%)  vasodilatation
- Bronchospasm (10%)
- AV block, atrial fibrillation
- Less common: headache, rapid arterial hypotension,
nausea, paresthesia

CONTRAINDICATION
- Second or third degree AV block
ANTI-ARRHYTHMICS CLASSIFICATION AND ACTIONS DRUG INTERACTIONS
DRUG CONDUCTION REPOLARIZATION/ AUTOMATICITY - Theophylline or Caffeine
VELOCITY REFRACTORINESS  If you give theophylline, effect of adenosine is
IA QUINIDINE ↓ ↑ ↓ lesser because the phosphodiesterase inhibitors
PROCAINAMIDE also block the adenosine
DISOPYRAMIDE - Dipyridamole
IB LIDOCAINE 0/↓ ↓/0 ↓  Inhibits uptake of adenosine greater effects
MEXILETINE
IC FLECAINIDE ↓↓ 0 ↓ 2. IVABRADINE
PROPAFENONE - Selective blocker of If (funny current)
II ACTION
ACETUBUTOLOL 0 0 0
ATENOLOL - Decreasing diastolic depolarizations of sinus node cells
BETAXOLOL - Reduces HR
BISOPROLOL - No effect on myocardial contractility, ventricular
CARTEOLOL repolarization or intracardiac conduction
CARVEDILOL
INDICATIONS
ESMOLOL
- Inappropriate sinus tachycardia
LABETALOL
METOPROLOL SIDE EFFECT
NADOLOL - Visual Disturbances
NEBUTOLOL
PENBUTOLOL 3. RANOLAZINE
PINDOLOL MECHANISM OF ACTION
PROPANOLOL - Blocks I Na and the late component of the Na+ current
TIMOLOL INaL
III AMIODARONE 0 ↑ 0 - Blocks the rapid component of delayed rectifier K+
DOFETILIDE channel IKr
DRONEDARONE
IBUTILIDE PHARMACOLOGICAL ACTION
SOTALOL - Ventricular myocyte: prolong APD and QT interval
IV DILTIAZEM, 0 0 0 - Atrial Myocyte: Prolong APD
VERAPAMIL
POSSIBLE INDICATION
- Not FDA approved
MISCELLANEOUS ANTI-ARRHYTHMIC AGENTS AND OTHER
DRUGS THAT ACT ON CHANNELS - Atrial and ventricular arrhythmias

1. ADENOSINE 4. MAGNESIUM
PHARMACOLOGICAL ACTIONS MECHANISM OF ACTION
- Gi receptor  decrease cAMP - Na+/K+/ATPase, Na, K, and Ca channel effect

[DOCUMEN
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SOURCES: Angel Trans, Pharmacology Lab Manual, Katzung, 2018 Doc Reyes lecture
 Far Eastern University- Nicanor Reyes Medical Foundation: Institute of Medicine
Course: PHARMACOLOGY
Topic: ANTI-ARRHYTHMITIC AGENTS [DOCUMENT TITLE]
00000000000000
INDICATION
- Digitalis-induced arrhythmia with hypomagnesemia
PATIENT-SPECIFIC ANTI-ARRHYTHMIC DRUG CONTRAINDICATIONS
- Torsades de pointes
CARDIAC CONDITIONS EXCLUDE/USE WITH CAUTION
5. ATROPINE Heart failure DISOPYRAMIDE
- Muscarinic antagonist  sympathetic will predominate FLECAINIDE
Sinus or AV node conduction DIGOXIN
PHARMACOLOGICAL ACTIONS
- Temporarily revert sinus bradycardia to normal sinus VERAPAMIL
rhythm and reverse AV nodal blocks by removing vagal DILTIAZEM
influences BETA RECEPTOR ANTAGONISTS
AMIODARONE
ADVERSE EFFECTS
Wolff-Parkinson-White DIGOXIN
- Tachycardia, pupil dilation, dry mouth, urinary retention,
Syndrome (WPW) VERAPAMIL
inhibition of sweating (anhidrosis), lured vision and
constipation DILTIAZEM
Infanodal Conduction NA+ CHANNEL BLOCKERS
CONTRAINDICATION Disease AMIODARONE
- Glaucoma Aortic/Subaortic Stenosis BRETYLIUM
INDICATION
History of MI FLECAINIDE
- Given for bradyarrhythmia but cannot be given for a long Prolonged QT Interval QUINIDINE
period of time because of its adverse effects PROCAINAMIDE
DISOPYRAMIDE
EVALUATION PRIOR TO ANTI-ARRHYTHMIC THERAPY SOTALOL
DOFETILIDE
- Identify and eliminate cause or precipitating factors
- Formulate a diagnosis IBUTILIDE
- Establish goals of treatment AMIODARONE
- Determine baseline condition Cardiac transplant ADENOSINE
- Determine need for therapy NON-CARDIAC CONDITIONS EXCLUDE/USE WITH CAUTION
- Minimize risks Diarrhea QUINIDINE
Prostatism, Glaucoma DISOPYRAMIDE
CLINICAL USES ANTI-ARRHYTHMICS Arthritis CHRONIC PROCAINAMIDE
CONDITION DRUG COMMENTS Lung Disease AMIODARONE
Sinus Class 2,4 Other underlying causes Tremor MEXILETINE
Tachycardia may need treatment Constipation VERAPAMIL
Atrial Class 1A, 1C, 2, 3, 4, Ventricular rate control is
Fibrillation/ Asthma, Peripheral Vascular BETA BLOCKERS,
Digitalis important goal;
Flutter Disease, Hypoglycemia PROPAFENONE
anticoagulation is required
Paroxysmal Class 1A, 1C, 2, 3, 4
Supraventricular Adenosine
Tachycardia
AV block Atropine Acute reversal
Ventricular Class 1, 2, 3
Tachycardia
Premature Class 2, 4 PVCs are often benign and
Ventricular Mg2+ salts do not require treatment
Complexes
Digitalis toxicity Class 1B
Mg2+ salts
KCl

[DOCUMEN
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SOURCES: Angel Trans, Pharmacology Lab Manual, Katzung, 2018 Doc Reyes lecture