Brief description of different antiarrhythmic agents along with their doses & indications in veterinary practice.

1. ANTIARRHYTHMIC AGENTS IN VETERINARY PRACTICE
PRESENTED BY
SINDHU K
MVSC SCHOLAR,
DEPT OF VPT,
COVAS, POOKODE.

2. ARRYTHMIA
Is an abnormality in the rate , regularity , or site of
origin of cardiac impulse or a disruption in impulse
conduction such that the normal sequence of atrial
& ventricular activation is changed.

3. ECG
Contraction
of atria
Contraction
of ventricles
Repolarization
of ventricles

4. Cardiac Na+ channels

5. Cardiac Action Potential
 Divided into five phases (0,1,2,3,4)
 Phase 4 - resting phase (resting membrane potential)
 Phase cardiac cells remain in until stimulated
 Associated with diastole portion of heart cycle
 Addition of current into cardiac muscle (stimulation) causes
 Phase 0 – opening of fast Na channels and rapid depolarization
 Drives Na+ into cell (inward current), changing membrane potential
 Transient outward current due to movement of Cl- and K+
 Phase 1 – initial rapid repolarization
 Closure of the fast Na+ channels
 Phase 0 and 1 together correspond to the R and S waves of the ECG

6. Cardiac Action Potential (con’t)
 Phase 2 - plateau phase
 sustained by the balance between the inward movement of Ca+ and outward
movement of K +
 Has a long duration compared to other nerve and muscle tissue
 Normally blocks any premature stimulator signals (other muscle tissue can accept
additional stimulation and increase contractility in a summation effect)
 Corresponds to ST segment of the ECG.
 Phase 3 – repolarization
 K+ channels remain open,
 Allows K+ to build up outside the cell, causing the cell to repolarize
 K + channels finally close when membrane potential reaches certain level
 Corresponds to T wave on the ECG

7. +30 mV
0 mV
-80 mV
-90 mV
OUTSIDE
MEMBRANE
INSIDE
Na+
0
4
3
2
1
K+
Ca++K+
At
p
K+
Na+
K+
Ca++
Na+
K+
Na+
Resting
open
Inactivated
Phase zero
depolarization
Early
repolarization
Plateau
phase
Rapid
Repolarization
phase
Phase 4
depolarization

8. etiology
 Ischemia/hypoxemia
 Imbalance of the parasympathetic & sympathetic
branches of the ANS
 Serum electrolyte imbalance[K+ & Ca ++]
 Activation of RAAS
 Pharmacologic therapy
 Inherited causes (rare)
 Arrhythmia associated with acquired heart diseases viz
CHF, viral myocarditis etc
 Infarction of the heart muscle

9. A: Contractile cell
B: Autorhythmic cell:
spontaneous depolarization at phase 4
Transmembrane Potentials of
Myocardial Cells

10. Alterations of normal automaticity
Autonomic neurotransmitters

11. .
 Structural & electrical remodeling, hemodynamic
changes & neuroendocrine signals each influence the
ion channel function, intracellular calcium response,
intercellular communications & matrix composition.
 Cardiac arrhythmias arise from 2 primary abnormality
1) Impulse initiation{spontaneous automaticity & triggered
activity}
2) Impulse propagation{conduction }

12. Impulse initiation
 Establishes heart rate
 Determined primarily by the rate of diastolic
depolarization ie., slope of phase 4
 In normal heart : heart rate is autonomically
controlled
Decreased by Acetylcholine release from
parasympathetic nerves &
Increased by Norepinephrine release from adrenal
cortex

13. b) Trigerred automaticity
+30 mV
0 mV
-80 mV
-90 mV
Delayed After
Depolarisation
(DAD)
Intracellular cal. Overload (Ischemia
reperfusion, adr.stress, digitalis intoxication or
heart failure)

14. Disturbances in automaticity
 Automatic cells of the SA node are dominant pacemaker ,
reaching threshold first with the resultant propagating impulse
exciting all other potential pacemaker cells before they
spontaneously attain threshold values
 If automaticity of the SA node is depressed/the spontaneous
firing rate in some other tissue (latent pacemaker)is accelerated ,
region of the heart other than SA node serves as pace maker &
initiates ectopic impulses

15. 1.The slope of phase 4 can be affected by a no of abnormal
conditions.
Enhanced automaticity occurs when the rate of spontaneous
diastolic depolarization increases sufficiently to allow
emergence of pathologically slowed or increased rates { sinus
tachycardia }
2.Ectopic foci(pace makers that normally are latent)
May emerge & may cause tachycardia if the frequency
exceeds that of sinoatrial node.

16. Less negative RMP
More negative TP
Ectopic pacemaker activity

17. a) Enhanced automaticity
Automatic behavior in sites ordinarily lacking
pacemaker activity
CAUSES:
Ischaemia/digitalis/catecholamines/acidosis/
hypokalemia/stretching of cardiac cells
Nonpacemaker nodal tissues: membrane
potential comes to -60mv
Increased slope of phase 4 depolarisation
Become ECTOPIC PACEMAKERS.(AV nodal
rhythm, idioventricular rhythm, ectopic beats)

18. 2 types of triggered arrhythmias occurs
1}Delayed after – depolarization : occurs after a normal action potential
& is followed by an overload of intracellular calcium
Eg : arrhythmias associated with myocardial failure , myocardial ischemia
, adrenergic stress , digoxin toxicity
2}Early after – depolarization : upstrokes occur during phase 3
repolarization & follow abnormally long action potentials.
Eg : results from abnormal inward sodium or calcium channel currents or
exchange pumps & associated with very slow heart rates or low
extracellular K+

19. `

20. Drugs MOA
 Drugs decreases the rate/slope of phase 4 spontaneous
depolarization ,suppressing the ectopic focus such that SA node
is allowed to resume its dominance , thus decreases
automaticity.
 Na+/Ca+ channel blockers ; more positive – lengthening the
time needed to attain threshold potential by increasing the
excitation threshold
 Hyperpolarisation ; more negative – by increasing the diastolic
membrane potential
 Shortening of the AP duration will inhibit EAD`s(magnesium also
inhibit EADs but MOA unknown)

21. Triggered activity:
Early/Delayed afterdepolarization

22. Disturbances in impulse conduction
 Associated with a phenomenon of REENTRY or CIRCUS movement.
 REENTRANT arrhythmias : anatomic
functional
 Anatomic arrhythmias involves 2/more pathways that travel to the
same region of the heart but differ in electrophysiology.
 Functional reentrant arrhythmias are exemplified by pathologies viz
ISCHEMIA that markedly slows conduction.

23. The concept of REENTRY(Schmidt & Erlanger 1929)
 Based on very slow conduction velocity
 An area of heart demonstrating unidirectional block of impulse
conduction
 Abnormally brief refractory period
 This theory holds that a cardiac impulse can travel circuitously around
an anatomic loop of fibers in which slowed conduction velocity & brief
refractoriness permit the impulse to arrive at cells that are no longer
refractory , there by permitting perpetual reexcitation

24. ,

25. Reentrant
Arrhythmias
 Anatomic or functional
reentrant circuit
 Unidirectional block on
one path;
 Slow conduction on the
other path
.

26. Drugs MOA
 Reentry can be controlled by drug that either creates bidirectional
block or bidirectional conduction through the region of cells causing
the unidirectional block
 Blocking specific ion channels {suppress initiation & automaticity}/ by
targeting autonomic functions thus altering initiation or conduction or
AP duration {thus refractory period}
 Drugs that facilitates adenosine / acetylcholine – thus increasing the
maximum diastolic or resting potential
 Drugs used to antagonize adrenergic receptors – thus decreasing the
slope of phase 4

27. .
TACHYARRHYTHMIAS BRADYARRHYTHMIAS
Atrial tachycardia , Sinus tachycardia Sinus arrest
Junctional tachycardia ,
supraventricular tachycardia
Sick sinus
Atrial flutter , atrial fibrillation AV - block
Ventricular fibrillation Cardiac arrest
Paroxysmal tachycardia

28. Arrhythmia Conditions
 Extrasystole: abnormal automaticity/after depolarization
 Paroxysmal Supraventricular Tachycardia: 150 - 200/minute (1:1), reentry
phenomenon (AV node)
 Atrial Flutter: 200-350/minute (2:1), reentrant circuit in right atrium
 Atrial Fibrillation: 350-550/min, electrophysiological inhomogenicity of
atrial muscles (bag of worms)
 Ventricular tachycardia: 4 or more consecutive extrasystole of ventricles
 Ventricular Fibrillation: rapid irregular contractions – fatal (MI,
electrocution)
 Torsades de pointes: polymorphic ventricular tachycardia, rapid
asynchronous complexes, rise and fall in baseline of ECG
 Atrio-ventricular Block (A-V Block): vagal influence or ischaemia - 1st, 2nd
and 3rd degree

29. Diagnostic Approaches to
Arrhythmias
 History and physical examination
 ECG
 Ambulatory ECG recording: Holter recording
 Exercise ECG: treadmill test
 Trans-esophageal electrophysiological study
 Invasive electrophysiological study (EPS)

30. Management of Arrhythmias
 Antiarrhythmic drugs
 Cardiac pacemakers
 DC cardioversion/defibrillation
 Implantable cardioverter/defibrillater (ICD)
 Radiofrequency catheter ablation
 Surgical operation

31. Classification of antiarrhythmic drugs
Grouped into 4 main classes according to SINGH VAUGHAN
WILLIAMS classification introduced in 1970.
 CLASS I : sodium channel blockers
 CLASS II : beta adrenoceptor antagonists
 CLASS III : potassium channel blockers
 CLASSIV : calcium channel blockers

32. +30 mV
0 mV
-80 mV
-90 mV
OUTSIDE
MEMBRANE
INSIDE
Na+
0
4
3
2
1
K+
Ca++K+
At
p
K+
Na+
K+
Ca++
Na+
Na+Ca++K+
RATE
SLOPE
Effective Refractory Period
RMP
THRESHOLD POTENTIAL
Possible MOA of antiarrythmic agents

33. Vaughan Williams classification of
antiarrhythmic drugs
 Class I: block sodium channels
 Ia (quinidine, procainamide, disopyramide)
AP
 Ib (lignocaine) AP
 Ic (flecainide) AP
 Class II: β-adrenoceptor antagonists (propranolol,
sotalol)
 Class III: prolong action potential and prolong
refractory period (suppress re-entrant rhythms)
(amiodarone, sotalol)
 Class IV: Calcium channel antagonists. Impair
impulse propagation in nodal and damaged
areas (verapamil, diltiazem)
.
Phase 4
Phase 0
Phase 1
Phase 2
Phase 3
0 mV
-80mV
II
I
III
IV
`

34. Class I : Na channel blockers
 Class I A drugs : quinidine, procainamide, disopyramide
 Class I B drugs : lidocaine, mexiletine, tocainide, phenytoin,
aprindine
 Class I C drugs : flecainide, propafenone, moricizine,
encainide, indecainide

35. 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

36. Class IA

37. QUINIDINE
 Prototype class IA
 Quinidine is an alkaloid obtained from cinchona bark & is
dextro-isomer of antimalarial drug quinine
 MOA
1) Blocks myocardial Na+ channels in frequency of use
dependent manner
2) Intermediate association with open/inactivated Na channels &
intermediate rate of dissociation from resting channels.
3) Prolongs AP due to K+ channel block
4) @ high conc, quinidine also inhibits L type Ca++ channels

38. PK of quinidine
 Nearly completely absorbed from GIT after oral administration
 Under goes hepatic first pass effect
 Following I/V administration rapidly passed from blood &
distributes into tissues, except brain.
 Highly protein bound (~90%)
 Metabolized in liver by hydroxylation
 Serum ½ life: 6 hours dogs & swine
2 hours cats
2.5 hours cattle
8 hours horses
1 hour goats

39. Adverse effects
 Dogs & cats : anorexia, nausea, vomiting, diarrhea.
 Horses : swelling of nasal mucosa, urticarial wheals & laminitis
 Sinus tachycardia, increased ventricular rates in patients atrial
fibrillation, hypotension, syncope, pro arrhythmic effects
 OVER DOSAGE : depressed automaticity & conduction/
tachyarrhytmias
 QUINIDINE TOXICITY : 25% increase in duration of QRS complex,
atrioventricular block, acceleration of ventricular tachyarrythmia
 Dogs : therapeutic range @ 2.5 – 5 micro g/ml
toxic range @ > 10 micro g/ml

40. TREATMENT OF QUINIDINE TOXICITY
1)I/V administration of sodium lactate 1/6 M or sodium
bicarbonate may reduce cardiotoxic effects by increasing
quinidine protein binding
2)Supportive & symptomatic measures
Forced diuresis using fluids & diuretics along with reduction of
urinary pH may enhance the renal excretion of quinidine

41. Contraindications & interactions
 CI in complete AV block, intraventricular conduction defect,
aberrant ectopic impulses, myasthenia gravis, hepatic
impairment & drug sensitivity.
DRUG INTERACTIONS
 Increases digoxin, amiodarone, verapamil serum
concentration.
 Enhances negative inotropic & hypotensive effects of beta
adrenoceptor antagonists & calcium agonists
 Alkalinisation of urine decreases excretion
 Acidification of urine increases quinidine excretion

42. CLINICAL INDICATIONS
 EQUINES : treatment for supraventricular arrhythmias
 Dose @ 20mg/kg, PO, every 2 hours (maximal dose 60g
daily) by stomach tube until arrhythmia is abolished.
 SMALL ANIMALS : supraventricular arrhythmias associated
with anomalous conduction in WOLFF-PARKINSON WHITE
SYNDROME.
Acute atrial fibrillation
Dogs @ 6-20 mg/kg, PO, 3 to 4 times daily
Cats @ 4-8 mg/kg, IM, TID.

43. Procainamide
 Similar MOA like quinidine ; affects cardiac automaticity,
excitability, responsiveness & conduction.
 Vagolytic effects are minimal & doesn’t cause a-adrenergic
blockade/paradoxical acceleration.
 Contra-indicated in patients with 2nd / 3rd degree block &
with torsades de pointes
 Indicated for treatment of ventricular arrhythmia than atrial
 Dogs @ 8-30 mg/kg, PO, TID
@ 2-8mg/kg, slow IV over 5 min, then 10-40
microgram/kg/min IV infusion

44. Disopyramide
 Is structurally dissimilar from other antiarrhythmic agents
 Quinidine like class IA drug that has prominent cardiac
depressant & anticholinergic actions, but no a-adrenoceptor
blocking property.
 Not routinely used in veterinary medicine bcoz of its relatively
rapid elimination & short half life(<2 hours)
 disopyramide is considered to be 2nd / 3rd line agent for
veterinary use.
Dogs @ 6-15 mg/kg, PO, 3 to 4 times a day

45. Class IB drugs
 Lignocaine,
 phenytoin,
 mexiletine,
 tocainide,
 Phenytoin.

46. Lidocaine / Lignocaine
 Local anesthetic & prototypic class IB
 Used predominantly for emergency treatment of ventricular
arrhythmias & effective only when administered IV
 MOA : lidocaine directly interacts with the open/inactivated
Na+ channels & is relatively selective for partially depolarized
cells & those with longer AP duration.
 Markedly suppresses automaticity in purkinje fibres, improves
conduction in depolarized/stretched fibres by increasing RMP
to near normal values, as a result of improved conduction,
normal transmission is restored in areas of unidirectional blocks.

47. Indications
 Following a therapeutic IV bolus, the onset of action is seen
with in 2 min & lasts for 10-20 min.
 Lidocaine is one of the best antiarrhythmic drugs & first choice
for life saving tachyarrhythmias & for most ventricular
arrhythmias, principally ventricular tachycardia & ventricular
premature complexes
 Dogs @ 1-2mg/kg, IV bolus, followed by 30-50 microg/kg/min,
IV infusion
 Large animals @ 0.25-0.5 mg/kg, IV.

48. Mexiletine hcl
 Is structural analogue of lidocaine & reported to produce
enhanced antiarrhythmic effects when combined with either
quinidine or procainamide therapy
 Indicated especially frequent ventricular premature beats,
ventricular tachycardia & those induced by digitalis toxicity
 Mexiletine is contraindicated for cats
 Dogs @ 4-8 mg/kg, PO, TID
@ 3-5 mg/kg, IV, followed by 5-10 microg/kg/min, iv infusion

49. 1) TOCAINIDE : amide type local anesthetic
Indicated in dogs for long term control of ventricular
arrhythmias @ 15-20 mg/kg, PO, TID.
2) PHENYTOIN : an antiepileptic drug with class IB
antiarrhythmic effects.
Indicated for ventricular arrhythmia in dogs @
10mg/kg, IV, TID, usually in increments of 2-4mg/kg.
3) APRINDINE : effective in controlling pre-mature
ventricular beats & ventricular tachycardia
Dogs @ 0.1mg/kg IV infusion for 5 min, repeated at 10
min intervals till arrhythmia is controlled, followed by
3mg/kg PO TID

50. 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

51. 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

52. Class II : beta – adrenoceptor
antagonists
 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
 Propranolol, atenolol, esmolol, sotalol, timolol, carazol,
bisoprolol.

53. MOA
 Increasing the magnitude of Ca++ current & slowing its
inactivation
 Increases the magnitude of repolarizing K+ & Ca++ current
 Increases the pace maker current & under
pathophysiological conditions increases both DAD & EAD
mediated currents
 Positive inotropic effect
 In heart activity is mainly through inhibition of beta1
adrenergic receptors, inhibits effect of sympathetic NS by
reducing heart rate, decreases intracellular Ca++overload &
inhibiting after depolarization mediated automaticity.

54. 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

55. Class III drugs
↑APD & ↑RP
by blocking
the K+
channels

56. Class III : K+ channel blockers
 Amiodarone, dronedarone, bretylium,
bunaftine, ibutilide, nifekalant
 Amiodarone is Iodone containing agent
structurally related to thyroid hormone
thyroxine
 indicated in horses to treat atrial fibrillation @
5mg/kg/hr, IV, for 1 hour followed by 0.8
mg/kg/hr for 23 hour

57. Bretylium
 Complex electrophysiological effects : partly result of
blockade of norepinephrine release release fron adrenergic
nerve terminals in heart but major direct action is
prolongation of action potential duration & effective
refractory period due to K+ channel blockade.
 Indicated in life threatening ventricular arrhythmias in dogs
@ 5-20 mg/kg, IV
 In pigs used for protection against tachyarrhythmias
induced by general anesthesia @ 0.02mg/kg/min, IV
infusion.

58. Calcium channel blockers (Class IV)
• Inhibit the inward
movement of
calcium ↓
contractility,
automaticity , and
AV conduction.
• Verapamil &
diltiazem

59. Class IV : Ca++ channel blockers
1) Diphenylalkylamine derivatives : verapamil,
gallopamil
2) Benzothiazepine derivatives : diltiazem,
clentiazem
3) Dihydropyridine derivatives : nifedipine,
amlodipine

60. Diphenylalkylamine derivatives
 VERAPAMIL depresses CA mediated depolarization suppresses
automaticity in SA node, AV node & purkinji fibres resulting in
suppression of both ectopic & triggered mechanism
 Decreases intracellular free calcium concentration & reduces
the force of cardiac contraction causing vasodilation.
 Reflex sympathetic stimulation due to direct vasodilatory effect
partly counteracts the cardiac slowing action of verapamil.
 It is contraindicated in sick sinus syndrome, cardiogenic shock,
severe CHF, cardiac glycoside toxicity

61. indications
 Supraventricular tachyarrhythmias, sustained &
paroxysmal tachycardia, excessive ventricular
hypertrophy, atrial flutter & fibrillation.
 Humans – treatment of hypertension, angina pectoris,
cardiac arrhythmia & cluster headaches, also effective
medication for prevention of migrane.
 Dogs @ 1-5mg/kg/, PO, TID
@ 0.05-0.2 mg/kg slow IV over period of 2-5 min
followed by IV infusion 2-10 microgram/kg/min.

62. Benzothiazepine derivatives
 DILTIAZEM : Ca++ channel blocking activity in both myocardial &
smooth muscle cells.
 It prevents transmembrane influx of extracellular Ca++ ions in
myocardial cells & vascular smooth muscles producing
vasodilation, negative chronotropic, negative inotropic &
negative dromotropic effects
 Indicated for treatment of atrial fibrillation, supraventricular
tachycardias, hypertropic cardiomyopathy, systemic hypertension
 Dogs @ 0.5-1.25mg/kg, PO, TID
@ 0.25mg/kg, IV, over 2 min. dose may be repeated if
required

63. Dihydropyridine derivatives
 Nifedipine, amlodipine, nicardipine, nitrendipine,
felodipine
 These drugs have high affinity for vascular Ca++ channels
& have more potent vasodilator effect.
 Nifedipine is prototype drug mainly used as antianginal &
antihypertensive drug in human medicine. Has little
significance in veterinary practice.
 Amlodipine indicated in cats for systemic hypertension @
0.625-1.25 mg (total dose), PO, SID

64. Miscellaneous agents
 Cardiac glycosides – complex effect by virtue of prolongation
of the effective refractory period of AV node.
 Digoxin controls the ventricular response-rate & force in atrial
fibrillation, atrial flutter & supraventricular tachycardia.
 Digitalis glycosides in high doses are ANTIARRHYTHMIC

65. Adenosine
 ADENOSINE : modulates physiological process through 4
adenosine receptors subtypes A1,A2a,A2b,A3 all belonging
to super family G proteins
 Has extremely short duration of action in humans say 15 sec
 Activity is mediated by stimulation of specific time
dependent outward K+ current, which appears to be
identical to one stimulated by Ach.
 Contraindicated in 2nd & 3rd degree block, sick sinus
syndrome, hypotension & asthma.
 Use in veterinary medications is limited.

66. references
 HS SANDHU Essentials of veterinary pharmacology and
toxicology, 2nd edition.
 H RICHARD ADAMS Veterinary pharmacology and
therapeutics, 8th edition.
 GOOGLE IMAGES
 ONLINE SEARCH RELATED TOPICS

67. THANK YOU