ANTIARRHYTHMIC AGENTS IN VETERINARY PRACTICE

PRESENTED BY

SINDHU K

MVSC SCHOLAR,

DEPT OF VPT,

COVAS, POOKODE.

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.

ECG

Contraction of atria

Contraction of ventricles

Repolarization of ventricles

Cardiac Na+ channels

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

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

+30 mV

0 mV

-80 mV

-90 mV

OUTSIDE

MEMBRANE

INSIDE

Na+

0

4

3

21

K+ Ca++K+

Atp

K+Na+

K+

Ca++

Na+

K+

Na+

Resting

open

Inactivated

Phase zero depolarizati

on

Early repolarizati

on

Plateau phase

Rapid Repolarizati

on phase

Phase 4 depolarizati

on

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

A: Contractile cellB: Autorhythmic cell:spontaneous depolarization at phase 4

Transmembrane Potentials of Myocardial Cells

Alterations of normal automaticity

Autonomic neurotransmitters

.

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 }

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

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)

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

.

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.

3.Arrhythmias of initiation may also be triggered by an

abnormal depolarization (phase O) , resulting in secondary

upstrokes in the action potential

Less negative RMP

More negative TP

Ectopic pacemaker activity

a) Enhanced automaticityAutomatic behavior in sites ordinarily lacking pacemaker activityCAUSES: 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)

.

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+

`

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)

Triggered activity: Early/Delayed afterdepolarization

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.

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

,

Reentrant Arrhythmias

Anatomic or

functional reentrant

circuit

Unidirectional block

on one path;

Slow conduction on

the other path

.

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

.

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

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

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)

Management of Arrhythmias

Antiarrhythmic drugs Cardiac pacemakers DC cardioversion/defibrillation Implantable cardioverter/defibrillater (ICD) Radiofrequency catheter ablation Surgical operation

Classification of antiarrhythmic drugsGrouped 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

+30 mV

0 mV

-80 mV

-90 mV

OUTSIDE

MEMBRANE

INSIDE

Na+

0

4

3

21

K+ Ca++K+

Atp

K+Na+

K+

Ca++

Na+

Na+Ca++K+

RATE

SLOPE

Effective Refractory Period

RMP

THRESHOLD POTENTIAL

Possible MOA of antiarrythmic agents

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

IIII

IV

`

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

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

Class IA

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

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

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

.

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

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

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.

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

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

Class IB drugs

Lignocaine,

phenytoin,

mexiletine,

tocainide,

Phenytoin.

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.

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.

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

.

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

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

Ia Ib IcModerate 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

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.

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.

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

Class III drugs

↑APD & ↑RP by blocking the K+ channels

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

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.

Calcium channel blockers (Class IV)

• Inhibit the inward movement of calcium ↓ contractility, automaticity , and AV conduction.

• Verapamil & diltiazem

Class IV : Ca++ channel blockers

1) Diphenylalkylamine derivatives : verapamil,

gallopamil

2) Benzothiazepine derivatives : diltiazem,

clentiazem

3) Dihydropyridine derivatives : nifedipine,

amlodipine

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

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.

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

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

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

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.

references

HS SANDHU Essentials of veterinary pharmacology and toxicology, 2nd edition.

H RICHARD ADAMS Veterinary pharmacology and therapeutics, 8th edition.

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