2. Antiarrhythmics ????
– In a textbook Interesting but sedative.
• Try it if you have insomnia
–In the lecture Confusion ??????????
• As always
–In the exam hall Panic!
• Don’t worry rarely asked
3. • A-RHYTHM –IA
• Defn- Arrhythmia is deviation of heart from
normal RHYTHM.
• RHYTHM
1) HR- 60-100
2) Should origin from SAN
3) Cardiac impulse should propagate through
normal conduction pathway with normal
velocity.
5. 100
60
Normal range
150 Simple tachyarrythmia
200 Paroxysmal TA
350 Atrial flutter
. 500 Atrial fibrillation
40 Mild bradyarrhythmias
20 moderate BA
Severe BA
7. Electrophysiology of cardiac tissue
• Impulse generation and transmission
• Myocardial action potential
• Depolarization and repolarization waves as
seen in ECG
8. Types of cardiac tissue
(on the basis of impulse generation)
• AUTOMATIC/ PACEMAKER/ CONDUCTING
FIBRES
(Ca++ driven tissues)
Includes SA node, AV node, bundle of His,
Purkinje fibres
Capable of generating their own impulse
Normally SA node acts as Pacemaker of heart
• NON-AUTOMATIC MYOCARDIAL CONTRACTILE
FIBRES (Na+ driven tissues)
Cannot generate own impulse
Includes atria and ventricles
15. Fast channel Vs slow channel AP
Fast channel AP
• Occurs in atria, ventricles, PF
• Predominant ion in phase-0
is Na+
• Conduction velocity more
• Selective channel blocker is
tetradotoxin , LA
Slow channel AP
• Occurs in SA node, A-V node
• Predominant ion in phase-0
is Ca2+
• Less
• Selective channel blockers
are calcium channel
blockers
16. Common terms
• Automaticity
– Capacity of a cell to undergo spontaneous
diastolic depolarization
• Excitability
– Ability of a cell to respond to external stimulus by
depolariztion
• Threshold potential
– Level of intracellular negativity at which abrupt
and complete depolarization occurs
17. Common terms
• Conduction velocity of impulse
– Determined primarily by slope of action potential
and amplitude of phase-0, any reduction in slope
leads to depression of conduction
• Propagation of impulse
– Depends on ERP & Conduction velocity
20. ECG is used as a rough guide to some
cellular properties of cardiac tissue
• P wave: atrial depolarization
• PR-Interval reflects AV nodal conduction time
• QRS DURATION reflects conduction time in
ventricles
• T-wave: ventricular repolarization
• QT interval is a measure of ventricular APD
30. Requirements for re-entry circuit
• Presence of anatomically defined circuit
• Region of unidirectional block
• Re-entry impulse with slow conduction
32. WPW: Initiation of SVT
Supraventricular tachycardia
• initiated by a closely
coupled premature atrial
complex (PAC)
• blocks in the accessory
pathway
• but conducts through the
AV node
• retrograde conduction via
accessory pathway
• inverted P wave produced
by retrograde conduction
visible in the inferior ECG
leads
33. Regulation by autonomic tone
Parasympathetic/Vagus Nerve
stimulation:
• Ach binds to M2 receptors
• Activate Ach dependent outward K+
conductance (thus hyperpolarisation)
• ↓ phase 4 AP
Sympathetic stimulation:
• Activation of β1 receptors
• Augmentation of L-type Ca2+ current
• Phase 4 AP more steeper
35. Classification of Anti-Arrhythmic Drugs
(Vaughan-Williams-Singh..1969)
Phase 4
Phase 0
Phase 1
Phase 2
Phase 3
0 mV
-
80m
V
II
I
III
IV
Class I: block Na+ channels
Ia (quinidine, procainamide,
disopyramide) (1-10s)
Ib (lignocaine) (<1s)
Ic (flecainide) (>10s)
Class II: ß-adrenoceptor antagonists
(atenolol, sotalol)
Class III: prolong action potential and
prolong refractory period
(amiodarone, dofetilide, sotalol)
Class IV: Ca2+ channel antagonists
(verapamil, diltiazem)
36. Classification based on clinical use
• Drugs used for supraventricular arrhythmia`s
– Adenosine, verapamil, diltiazem
• Drugs used for ventricular arrhythmias
– Lignocaine, mexelitine, bretylium
• Drugs used for supraventricular as well as
ventricular arrhythmias
– Amiodarone, - blockers, disopyramide,
procainamide
37. Na+ channel blocker
• Bind to and block Na+ channels (and K+ also)
• Act on initial rapid depolarisation (slowing effect)
• Local Anaesthetic (higher concentration): block
nerve conduction
• Do not alter resting membrane potential
(Membrane Stabilisers)
• At times, post repolarization refractoriness.
• Bind preferentially to the open channel state
• USE DEPENDENCE : The more the channel is in
use, the more drug is bound
38. Ia Ib Ic
Moderate Na channel
blockade
Mild Na channel
blockade
Marked Na channel
blockade
Slow rate of rise of
Phase 0
Limited effect on
Phase 0
Markedly reduces rate
of rise of phase 0
Prolong refractoriness
by blocking several
types of K channels
Little effect on
refractoriness as there
is minimal effect on K
channels
Prolong refractoriness
by blocking delayed
rectifier K channels
Lengthen APD &
repolarization
Shorten APD &
repolarization
No effect on APD &
repolarization
Prolong PR, QRS QT unaltered or
slightly shortened
Markedly prolong PR
& QRS
39. Class I: Na+ Channel Blockers
• IA: Ʈrecovery moderate (1-10sec)
Prolong APD
• IB: Ʈrecovery fast (<1sec)
Shorten APD in some heart
tissues
• IC: Ʈrecovery slow(>10sec)
Minimal effect on APD
41. Quinidine
• Historically first antiarrhythmic drug used.
• In 18th century, the bark of the cinchona plant
was used to treat "rebellious palpitations“
pharmacological effects
threshold for excitability
automaticity
prolongs AP
42. Quinidine
• Clinical Pharmacokinetics
• well absorbed
• 80% bound to plasma proteins (albumin)
• extensive hepatic oxidative metabolism
• 3-hydroxyquinidine,
• is nearly as potent as quinidine in blocking
cardiac Na+ channels and prolonging cardiac
action potentials.
43. Quinidine
• Uses
• to maintain sinus rhythm in patients with
atrial flutter or atrial fibrillation
• to prevent recurrence of ventricular
tachycardia or VF
45. Drug interactions
• Metabolized by CYP450
• Increases digoxin levels
• Cardiac depression with beta blockers
• Inhibits CYP2D6
46. Disopyramide
• Exerts electrophysiologic effects very similar to
those of quinidine.
• Better tolerated than quinidine
• exert prominent anticholinergic actions
• Negative ionotropic action.
• A/E-
• precipitation of glaucoma,
• constipation, dry mouth,
• urinary retention
47. Procainamide
• Lesser vagolytic action , depression of
contractility & fall in BP
• Metabolized by acetylation to N-acetyl
procainamide which can block K+ channels
• Doesn’t alter plasma digoxin levels
• Cardiac adverse effects like quinidine
• Can cause SLE not recommended > 6 months
• Use: Monomorphic VT, WPW Syndrome
48. Ia Ib Ic
Moderate Na channel
blockade
Mild Na channel
blockade
Marked Na channel
blockade
Slow rate of rise of
Phase 0
Limited effect on
Phase 0
Markedly reduces rate
of rise of phase 0
Prolong refractoriness
by blocking several
types of K channels
Little effect on
refractoriness as there
is minimal effect on K
channels
Prolong refractoriness
by blocking delayed
rectifier K channels
Lengthen APD &
repolarization
Shorten APD &
repolarization
No effect on APD &
repolarization
Prolong PR, QRS QT unaltered or
slightly shortened
Markedly prolong PR
& QRS
51. Lignocaine
• Blocks inactivated sodium channels more than
open state
• Relatively selective for partially depolarized
cells
• Selectively acts on diseased myocardium
• Rapid onset & shorter duration of action
• Useful only in ventricular arrhythmias ,
Digitalis induced ventricular arrnhythmias
52. • Lidocaine is not useful in atrial arrhythmias???
• atrial action potentials are so short that the
Na+ channel is in the inactivated state only
briefly compared with diastolic (recovery)
times, which are relatively long
53. Pharmacokinetics
• High first pass metabolism
• Metabolism dependent on hepatic blood flow
• T ½ = 8 min – distributive, 2 hrs – elimination
• Propranolol decreases half life of lignocaine
• Dose= 50-100 mg bolus followed by 20-40 mg
every 10-20 min i.v
55. • Local anaesthetic
• Inactive orally
• Given IV for antiarrhythmic action
• Na+ channel blockade which occurs
• Only in inactive state of Na+ channels
• CNS side effects in high doses
• Action lasts only for 15 min
• Inhibits purkinje fibres and ventricles but
• No action on AVN and SAN so
• Effective in Ventricular arrhythmias only
56. Mexiletine
• Oral analogue of lignocaine
• No first pass metabolism in liver
• Use:
– chronic treatment of ventricular arrhythmias
associated with previous MI
– Unlabelled use in diabetic neuropathy
• Tremor is early sign of mexiletine toxicity
• Hypotension, bradycardia, widened QRS ,
dizziness, nystagmus may occur
57. Tocainide
• Structurally similar to lignocaine but can be
administered orally
• Serious non cardiac side effects like
pulmonary fibrosis, agranulocytosis,
thrombocytopenia limit its use
58. Class I C drugs
Encainide, Flecainide, Propafenone
Have minimal effect on
repolarization
Are most potent sodium
channel blockers
• Risk of cardiac arrest ,
sudden death so not used
commonly
• May be used in severe
ventricular arrhythmias
60. Propafenone class 1c
• Structural similarity with propranolol & has -
blocking action
• Undergoes variable first pass metabolism
• Reserve drug for ventricular arrhythmias, re-
entrant tachycardia involving accesory
pathway
• Adverse effects: metallic taste, constipation
and is proarrhythmic
61. Flecainde (Class Ic)
• Potent blocker of Na & K channels with slow
unblocking kinetics
• Blocks K channels but does not prolong APD & QT
interval
• Maintain sinus rhythm in supraventricular
arrhythmias
• Cardiac Arrhythmia Suppression Test (CAST Trial):
When Flecainide & other Class Ic given
prophylactically to patients convalescing from
Myocardial Infarction it increased mortality by 2½
fold. Therefore the trial had to be prematurely
terminated
62. Class II: Beta blockers
• -receptor stimulation:
• ↑ automaticity,
• ↑ AV conduction velocity,
• ↓ refractory period
• -adrenergic blockers competitively block
catecholamine induced stimulation of cardiac
- receptors
63. Beta blockers
• Depress phase 4 depolarization of pacemaker
cells,
• Slow sinus as well as AV nodal conduction :
– ↓ HR, ↑ PR
• ↑ ERP, prolong AP Duration by ↓ AV
conduction
• Reduce myocardial oxygen demand
• Well tolerated, Safer
64. β Adrenergic
Stimulation
β Blockers
↑ magnitude of Ca2+ current &
slows its inactivation
↓ Intracellular Ca2+ overload
↑ Pacemaker current→↑
heart rate
↓Pacemaker current→↓
heart rate
↑ DAD & EAD mediated
arrhythmias
Inhibits after-depolarization
mediated automaticity
Epinephrine induces
hypokalemia (β2 action)
Propranolol blocks this action
65.
66. Use in arrhythmia
• Control supraventricular arrhythmias
• Atrial flutter, fibrillation, PSVT
• Treat tachyarrhythmias caused by adrenergic
• Hyperthyroidism Pheochromocytoma,
during anaesthesia with halothane
• Digitalis induced tachyarrythmias
• Prophylactic in post-MI
• Ventricular arrhythmias in prolonged QT
syndrome
+
67. Esmolol
• β1 selective agent
• Very short elimination t1/2 :9 mins
• Metabolized by RBC esterases
• Rate control of rapidly conducted AF
• Use:
• Arrythmia associated with anaesthesia
• Supraventricular tachycardia
70. Amiodarone
• Iodine containing long acting drug
• Mechanism of action: (Multiple actions)
–Prolongs APD by blocking K+ channels
–blocks inactivated sodium channels
–β blocking action , Blocks Ca2+ channels
–↓ Conduction, ↓ectopic automaticity
71. • Pharmacokinetics:
–Variable absorption 35-65%
–Slow onset 2days to several weeks
–Duration of action : weeks to months
• Dose
–Loading dose: 150 mg over 10min
–Then 1 mg/min for 6 hrs
–Then maintenance infusion of 0.5 mg/min
for 24 hr
Amiodarone
72. Amiodarone
• Uses:
– Can be used for both supraventricular and
ventricular tachycardia
• Adverse effects:
– Cardiac: heart block , QT prolongation, bradycardia,
cardiac failure, hypotension
– Pulmonary: pneumonitis leading to pulmonary
fibrosis
– Bluish discoloration of skin, corneal microdeposits
– GIT disturbances, hepatotoxicity
– Blocks peripheral conversion of T4to T3 can cause
hypothyroidism or hyperthyroidism
73. • Antiarrhythmic
• Multiple actions
• Iodine containing
• Orally used mainly
• Duration of action is very long (t ½ = 3-8 weeks)
• APD & ERP increases
• Resistant AF, V tach, Recurrent VF are indications
• On prolonged use- pulmonary fibrosis
• Neuropathy may occur
• Eye : corneal microdeposits may occur
74. • Bretylium:
– Adrenergic neuron blocker used in resistant
ventricular arrhythmias
• Sotalol:
– Beta blocker
• Dofetilide, Ibutilide :
– Selective K+ channel blocker, less adverse events
– use in AF to convert or maintain sinus rhythm
– May cause QT prolongation
75. Newer class III drugs
• Dronedarone
• Vernakalant
• Azimilide
• Tedisamil
76. Calcium channel blockers (Class IV)
• Inhibit the inward
movement of calcium
↓ contractility,
automaticity , and AV
conduction.
• Verapamil & diltiazem
77. Verapamil
• Uses:
– Terminate PSVT
– control ventricular rate in atrial flutter or
fibrillation
• Drug interactions:
– Displaces digoxin from binding sites
– ↓ renal clearance of digoxin
78. Other antiarrhythmics
• Adenosine :
– Purine nucleoside having short and rapid action
– IV suppresses automaticity, AV conduction and
dilates coronaries
– Drug of choice for PSVT
– Adverse events:
• Nausea, dyspnoea, flushing, headache
80. Adenosine
• Acts on specific G protein-coupled adenosine
receptors
• Activates AcH sensitive K+ channels channels in SA
node, AV node & Atrium
• Shortens APD, hyperpolarization & ↓ automaticity
• Inhibits effects of ↑ cAMP with sympathetic
stimulation
• ↓ Ca currents
• ↑AV Nodal refractoriness & inhibit DAD’s
81. • Atropine: Used in sinus bradycardia
• Digitalis: Atrial fibrillation and atrial flutter
• Magnesium SO4: digitalis induced arrhythmias
Other antiarrhythmics
82. Magnesium
• Its mechanism of action is unknown but may
influence Na+/K+ATPase, Na+ channels,
certain K+ channels & Ca2+ channels
• Use: Digitalis induced arrhythmias if
hypomagnesemia present, refractory
ventricular tachyarrythmias, Torsade de
pointes even if serum Mg2+ is normal
• Given 1g over 20mins
Deviation from the normal pattern of cardiac rhythmMay occur when there is disturbance in initiation or conduction of cardiac impulse Range from asymptomatic to life threatening
Non automatic fibres: these are ordinary working myocardial fibres, cannot generate the impulse of their own, during diastole RMP remains stable -90mV inside. When stimulated they depolarize rapidly (Fast phase-0) with considerable overshoot (+30mV), rapid return to near isoelectric level 0mV (Phase-1), maintenance of membrane potential at this level for a considerable period of time (Phase-2) plateau phase during which calcium ions flow in and bring about contraction, then relatively rapid repolarization (Phase-3) mainly by continued extrusion of potassium via potassium channel, phase 4 resting phase, in this phase the final ionic reconstitution of cell is achieved by na-k+ exchange pump which actively pushes Na+ out of cell and K+ into the cell. The resting membrane potential once attained doesnot decay (stable- phase4). Automatic fibres: they are present in SA node, AV node and his-purkinje system. i.e the specialized conducting tissue(in addition patches are present around interatrial septum, A-V ring and around openings of great veins. The most charecteristic feature of these fibres is the phae 4 or slow diastolic depolarization i.e after repolarizing to the maximum value membrane potential decays spontaneously when it reaches a critical threshold value –sudden depolariztion occurs automatically . Thus they are capable of generating their own impulse. The rate of impulse generation by a particular fibre depends upon the value of maximum diastolic potential , slope of phase 4 depolarization and value of threshold potential . Why SA node acts as pacemaker: SA node has steepest phase-4 depolarization undergoes self excitation and propogates the implse to the rest of the heart- acts a pacemaker. Other fibres which also undergo phase 4 depolarization but at a slower rate receive propogatedimpulsebefore reaching threshold valueand remain as latent pacemakers.
RMP IS -90 MVCardiac boundedby a lipoprotein membrane which has receptor channels crossing itWHEN AN ATRIAL OR VENTRICULAR CELL RECIEVES An action potential it starts depolarising in response to it..and sodium starts entering itIntracellular negativity starts diminishingWhen such depolarisation reaches a threshold potential, the sodium channels open abruptlyNa enters cell in large quantitiesCELL MEMBRANE ACTION POTENTIAL CHANGES FROM -90 TO ALMOST +30MVPhase 0: rapid depolarisation…fast selective inflow of na ionsDuring latter part, ca ions also enter the cell via na channels Frther in phase 1 and 2 ca ions enter thru slow ca channelsTHE CONFORMATION OF THE SODIUM CHANNELS HENCE CHANGES TO INACTIVE STATEThe ca which enters the cell in dis manner causes release of ca from sarcoplasmicreticulumraising the conc of ca within the cellsThis intracellular free ca interacts with actinmyocin system and causes contraction of heartAfetr this, phase 1: short rapid repolarisation due to beginning of outflow of potassium and entry of cloride ions into the cells, MEMBRANE CHARGE CHANGES FROM +30 TO ALMOST 0 MV IN VERY SHORT TIMEPhase 2 : prolonged plateau phase.. Balance bw ca enterin the cell and k leavin the cell..VOLTAGE SENSITIVE SLOW l type CA CHANNELS OPEN …SLOW INWARD CA CURRENT BALANCED BY SLOW OUTWARD K CURRENT..DEPOLARISATION = REPOLARISATIONPhase 3 : rapid repolarisation.. CA CHANNELS CLOSE…K CHANNELS OPEN..Contimued extrusion of k…RESUMES INITIAL NEGATIVITYFROM PHASE 0 TO 3 THERE HAS BEEN A GAIN OF NA AND A LOSS OF K ..THIS IS NOW REVERTED AND BALANCED BY NA K ATPASEPhase 4: resting phase..ELECTRICALLY STABLE… Ionic reconstitution of cell is reachieved by na k exchange pumpRMP MAINTAINED BY OUTWARD K LEAK CURRENTS AND NA CA EXCHANGERSThe cycle is then repeatedInactivation gates of sodium channels in resting membranes close over the potential range of -75 to -55mvCardiac sodium channel protein shows 3 different conformationsDepolarisation to threshold voltage results in opening of the activation gates of sodium channel thus causing markerdly increased sodium permeabilityBrief intense sodium current , conductance of fast sodium channel suddenly increases in response to depolarisingstimulUsVery large influx of na accounts for phase 0 depolarisationClusure of inactivation gates resultRemain inactivated till mid phase 3 to permit a new propagated response to external stimulus…refractory period..Cardiac calcium channels are L typePhase 1 and 2 : turning off nodium current, waxing and waning of calcium curent, slow development of repolarising potassium current, calcium enters ..potassium leaves..Phase 3: complete inactivation of sodium and calcium currents and full opening of potassium 2 types of main potassium currents involved in phase 3 : ikr and iksCertain potassium channels are open at rest also…”inward rectifier” channelsIn addition there are 2 energy requiring exchange pumps in cardiac myocyte cell membrane…na k exchange pump…and andna-ca exchange pumpNormally na ions concentrated extracellularly and vice versa for k cionsThus have a tendency odf diffusion along concentration gradientThis diffusion is opposed by na k pumpThis pump operates contimuously and does not switch on and off during action potential of cardiac cells
Action potential in automatic tissuesless negative resting membrane potential ,Maximum diastolic potential lies near -60 mvslow diastolic depolarization (phase 4), which generates an action potential as the membrane voltage reaches thresholdaction potential upstrokes (phase 0) are slow(mediated by calcium rather than sodium current)Action potential is longerConduction velocity is slow, Refractory period longerLess overshoot low amplitude RMP not stable and full repolarisation at -60mVPhase 1 2 3 indistinguishable Spontaneous Depolarisation occurs due to: Slow, inward Ca2+ currents Slow, inward Na+ currents called “Funny Currents”Ca influx and not of na dominates the depolarisation and is largely responsible for initiation and propagation of apThus cardiac automaticity is decreased by calcium channel blockers in case of slow channel AP Steeper the diastolic depolarisation, higher is the pacemaker rateSA node has the steepest phase 4 depolarisationOther nodal cells can become pacemakers when their own intrinsic rate of depolarisation is greater than SA node(latent pacemakers)In all pacemaker cells, the outward potassium current during phase 4 is smaller, which keeps the cell with automaticity in a less negative potential (near depolarisation state -60mv).The depolarising inward calcium currents are large enough to gradually depolarise the cell during diastoleVagal discharge and beta blockers slow the phase 4 slopeTachycardia is caused by increased paceamkers discharge ..due to increased phase 4 slope..reasons may be: hypokalemia, beta stimulation, positive chronotropic drugs, fibrestrech, acidosis, partial depolarisation by currents of injury
Coronary sinus opening also ERP< APD in fast channel, ERP> APD in slow channel , slow channel AP can occur in purkinjefibres also, but it has much longer duration with prominent plateu phase.
In normal heart automaticity is maximum in SA node (Pacemaker). In diseased heart, other areas of myocardium may may develop automaticity and become focus of ectopic impulse generation and arrhythmias. Excitability: can be conceived in terms of minimum intensity of stimulus required to depolarize the cell membrane. It depends upon the level of resting(diastolic) intracellular negativity, if negeativity decreases eg from -90mV TO -70mV excitability of cell increases. Threshold potential: if threshold potential is raised changed from -70 to -60 mV Automaticity of tissue is supressed.
A drug which reduces phase zero slope(at any given RMP) will shift membrane responsiveness curve to right and impede the conduction. Reverse occurs if a drug shifts curve to left. Normally purkinjefibres have highest conduction velocity 4000 mm/sec
Protective mechanism and keeps the heart rate in check, prevents arrhythmias and coordinates muscle contractionIt extends from phase 0 uptill sufficient recovery of Na channels. Divided into:
Ectopic pacemaker activity is encouraged by Faster phase 4 depolarization due to ishemiaLess negative resting membrane potential More negative threshold potential due to ishemia
After depolarizations are secondary depolarizations accompanying normal or premature action potentials. Early AfterdepolarizationPhase 3 of repolarization interruptedResult from inhibition of Delayed Rectifier K+ CurrentMarked prolongation of Action PotentialSlow heart rate, ↓ Extracellular K+, Drugs prolonging APDDEPRESSION OF DELAYED RECTIFIER POTASSIUM CURRENTREPOLARISATION DURING PHASE 3 IS INTERRUPTEDMEMBRANE POTENTIAL OSSILATESMarkedly prolongs cardiac repolarisation…development of polymorphic ventricular tachycardia…with long qt interval…known as torsades de pointes syndrome..Some drugs may give rise to ead..and thus torsades..If amplitude of these ossilations is sufficiently large..neighbouring tissue is activated..series of impulses are propagatedThus slow repolarisationLong APAssociated with long QT intervalProminent among the factors that modulate phase 4 is autonomic nervous system tone. The negative chronotropic effect of activation of the parasympathetic nervous system is the result of release of acetylcholine that binds to muscarinic receptors, releasing G protein subunits that activate a potassium current (IKACh) in nodal and atrial cells. The resulting increase in K+ conductance opposes membrane depolarization, slowing the rate of rise of phase 4 of the action potential. Conversely, augmentation of sympathetic nervous system tone increases myocardial catecholamine concentrations, which activate both and receptors. The effect of 1-adrenergic stimulation predominates in pacemaking cells, augmenting both L-type Ca current (ICa-L) and If, thus increasing the slope of phase 4. Enhanced sympathetic nervous system activity can dramatically increase the rate of firing of SA nodal cells, producing sinus tachycardia with rates >200 beats/min. By contrast, the increased rate of firing of Purkinje cells is more limited, rarely producing ventricular tachyarrhythmias >120 beats/min.abnormal impulse formation is due to the development of triggered activity. Triggered activity is related to cellular afterdepolarizations that occur at the end of the action potential, during phase 3, and are referred to as early afterdepolarizations, or they occur after the action potential, during phase 4, and are referred to as late afterdepolarizations. Afterdepolarizations are attributable to an increase in intracellular calcium accumulation. If sufficient afterdepolarization amplitude is achieved, repeated myocardial depolarization and a tachycardic response can occur. Early afterdepolarizations may be responsible for the VPCs that trigger the polymorphic ventricular arrhythmia known as torsades des pointes (TDP). Late afterdepolarizations are thought to be responsible for atrial, junctional, and fascicular tachyarrhythmias caused by digoxin toxicity and also appear to be the basis for catecholamine-sensitive VT originating in the outflow tract. In contrast to automatic tachycardias, tachycardias due to triggered activity (Fig. 226-2B ) can frequently be provoked with pacing maneuvers.
Late AfterdepolarizationsSecondary deflection after attaining RMPIncreased intracellular Ca2+ overloadAdrenergic stress, digitalis intoxication, ischemia-reperfusionAFTRE attaining Resting membrane potential, a secondary deflection occurs..If this reaches threshold potential..it initiates a single premature APGENERALLY OCCURS FROM CALCIUM OVERLOAD..digitalis toxicity..ischaemia reperfusion
Requirements for a reentry circuitPresence of an anatomically defined circuitHeterogeneity in refractoriness among regions in the circuitSlow conduction In one part of circuitReentry is underlying mechanism for premature beats, paroxysmal supraventricular tachycardia, atrial flutter, ventricular fibrillation
Anatomically defined re-entrnt pathway , patients have accesory pathway known as bundle of kent
Surprisingly few mechanisms of antiarythmic actionIn general these drugs have these action..they act by altering..Rate of phase 0 depolarisationSlope of phase 0 depolarisation..blocks reentrant impulses…quinidine, procainamide, disopyramide, lignocaine and verapamilposess this actionIncreasing the effective refractory period..thus duration of action potential..and blocking reentrant impulses…quinidine, procainamide, propanolol and potassium posess this actionMaking the resting membrane potential even more negative and decreasing the slope of phase 4..thus supressing automaticity…this action is shown by all antiarrythmic drugs….it supresses the enhanced automaticity of ectopic foci ..examples are lignocaine and phenytoinMaking the threshold potential less negative i.e. shifting it towards 0…again supresses enhanced automaticity of ectopic focii..quinidine..procainamide, propanolol and potassium posess this actionIn general, altering the na and ca channels, alter the threshold potential and altering the potassium channels will alter the length of refractory period and thus duration of action potential
↓ Automaticity ↓ Excitability↓ Conduction velocity Refractory period Direct action : prolonged in all cardiac tissues Vagolytic action : Atria: ↑AV node : ↓Ventricles : unaltered Over all : ↑ atrial , ↑ ventricular, ↓ AV node Contractility BPECG ExtracardiacDepresses skeletal muscle Quinine like antimalarial , antipyretic and oxytocic action
Prominent cardiac depressant and antivagal action Use: second line drug for preventing recurrences of ventricular arrhythmia No affect on sinus rate due to opposing actions Can also cause mental depression, erectile dysfunction, and hypotension
50 % EXCRETED UNCHANGED IN URINEAlso discuss about procaine
Class Ib drug blocks sodium channels more in inactivated state than open state but do not delay the channel recovery they do not deprss AV condcution or prolong APD Even shorten Than with long APD ( Na + channels remain inactivated for long period of time Normal ventricular fibres are minmally affected , depolarized damaged fibres are significantly depressed Brevity of AP and lack of lidocaine effect on channel recovery may explain its inefficacy in atrial arrhythmias No significant hemodynamic effectNo significant autonomic actions
IV preparation must not contain preservative , symapthomimetic or vasoconstrictor1-3 mg/min infusion Clinical Pharmacokinetics High first pass metabolism half-life 1–2 hoursa loading dose of 150–200 mg administered over about 15 minutes should be followed by a maintenance infusion of 2–4 mg/min
400 mg loading dose then 200 mg 8hrlyContraindicated in patients with AV block as it may accelerate AV block 450- 750 mg of mexiletine orally per day provides significant relief in diabetic neuropathy
Although uses are similar to lidocaine3:1000Can also cause nausea, dizziness, paraesthesia, numbness
Can precipitate CHF by depressing AV CONDUCTION and ALSO CAN CAUSE bronchospasm. Dose = 200 mg tdsMorcizine has properties of all 3 classes but as it prolongs qrs it has been placed along with class Ic drugs
Usual dose = 100- 200 mg bd orally how ever these drugs are proarrhythmic even when normal doses are administered to patients with sick sinus syndrome pre exixting ventricular tachyarrhythmia, ventricular ectopy or previous MI Currently reserved for life threatening refractory ventricular arrhythmias who do not have CORONARY ATRETY DISEASE. LIKELY HOOD OF DEVELOPING TORSADES DE POINTES IIS SERIOUS DRAWBACK OF THESE DRUGS, OTHER ADVERSE EFFECTS INCLUDE VISUAL DISTURBANCES , DIZZINESS, NAUSEA AND HEADACHE.
Beta receptor stimulation causes increased automaticity, steeper phase 4, Increased AV conduction velocity and decreased refractory period Beta adrenergic blockers competitively block catecholamine induced stimulation of cariac beta receptors, slow
Slow sinus as well as av nodal conduction which results in decrease in HR and increase PR atrial depolarization, QT and QRS are not significantly altered.
Propranolol, acebutololesmolol have been aprroved for antiarrhythmic use
Class III drugs block outward K+ channels during phase III of action potential These drugs prolong the duration of action potential without without affecting phase 0 of action potential or resting membrane potential they instead prolong ERP
HENCE IT DECREASES HEART RATE AS WELL AS av conduction, better efficacy with lower risk of development of Torsades de pointes
Many drug interactions
Bretylium became obsolete because of poor bioavailability and development of tolerance, reintroduced as antiarrhythmic for parenteral use. Main adverse effect is postural hypotension , nausea, vomiting . Long term use may result in swelling of parotid gland particularly at meal time. It is contraindicated in digitalis induced arrhythmias and cardiogenic shock.
Dronaderone: amiodarone like drug without iodine atoms so no pulmonary or thyroid toxicity. Has shorter half life 1-2 days compared to months Vernakalant mixed sodium and potassium channel blocker Azimilide: blocks rapid and slow components of potassium channels low incidence of torsades de pointes Tedisamil: