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Cardiac Arrhythmias:
- 25% treated with digitalis
- 50% anesthetized patients
- 80% patients with AMI
reduced cardiac output
drugs or nonpharmacologic:
- pacemaker, cardioversion, catheter ablation, surgery
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
ELECTRO-PHYSIOLOGY
OF
NORMAL
CARDIAC
RHYTHM
SA node
AV node
ATRIA
His-Purkinje System
VENTRICLES
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
IONIC BASIS OF MEMBRANE ELECTRICAL ACTIVITY
Transmembrane potential of cardiac cells is determined by the concentrations of the ff. ions:– Sodium, Potassium, Calcium
The movement of these ions produces currents that form the basis of the cardiac action potential
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
PHASES OF ACTION POTENTIAL
Phase 0
>Rapid depolarization
>Opening fast Na+
channels→ Na+ rushes in →depolarization
Phase 1
>Limited depolarization
>Inactivation of fast
Na+ channels→ Na+
ion conc equalizes
>↑ K+ efflux & Cl- influx
Phase 2
>Plateau Stage
>Cell less permeable to Na+
>Ca++ influx through slow Ca++ channels
>K+ begins to leave cell
Phase 3
>Rapid repolarization
>Na+ gates closed
>K+ efflux
>Inactivation of slow Ca++ channels
Phase 4
>Resting Membrane Potential
>High K+ efflux
>Ca++ influx
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
MECHANISMS OF ARRHYTHMIA
ARRHYTHMIA – absence of rhythm
DYSRRHYTHMIA – abnormal rhythm
ARRHYTHMIAS result from:
1. Disturbance in Impulse Formation
2. Disturbance in Impulse Conduction Block results from severely depressed conduction Re-entry or circus movement / daughter impulse
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
FACTORS PRECIPITATING CARDIAC ARRHYTHMIAS:
1. Ischemia pH & electrolyte abnormalities 80% – 90% asstd with MI
2. Excessive myocardial fiber stretch/ scarred/ diseased cardiac tissue
3. Excessive discharge or sensitivity to autonomic transmitters
4. Excessive exposure to foreign chemicals & toxic substances 20% - 50% asstd with General Anesthesia 10% - 20% asstd with Digitalis toxicity
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Supraventricular:- Atrial Tachycardia
- Paroxysmal Tachycardia
- Multifocal Atrial Tachycardia
- Atrial Fibrillation
- Atrial Flutter
Ventricular:- Wolff-Parkinson-
White (preexcitation syndrome)
- Ventricular Tachycardia
- Ventricular Fibrillation- Premature Ventricular
Contraction
ARRHYTHMIAS:
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
CLASS I: Sodium Channel Blocking Drugs IA - lengthen AP duration
- Intermediate interaction with Na+ channels- Quinidine, Procainamide, Disopyramide
IB - shorten AP duration- rapid interaction with Na+ channels- Lidocaine, Mexiletene, Tocainide, Phenytoin
IC - no effect or minimal AP duration - slow interaction with Na+ channels- Flecainide, Propafenone, Moricizine
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Increase AV nodal conduction Increase PR interval Prolong AV refractoriness Reduce adrenergic activity Propranolol, Esmolol, Metoprolol,
Sotalol
CLASS II: BETA-BLOCKING AGENTS
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Prolong effective refractory period by prolonging Action Potential – Amiodarone - Ibutilide – Bretylium - Dofetilide– Sotalol
CLASS III: POTASSIUM CHANNEL BLOCKERS
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
CLASS IV: CALCIUM CHANNEL BLOCKERS
Blocks cardiac calcium currents
→ slow conduction
→ increase refractory period
*esp. in Ca++ dependent tissues (i.e. AV node)
Verapamil, Diltiazem, Bepridil
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Miscellaneous: ADENOSINE → inhibits AV conduction &
increases AV refractory period
DIGITALIS → Indirectly alters autonomic outflow
MAGNESIUM → Na+/K+ ATPase, Na+, K+, Ca++ channels
POTASSIUM → normalize K+ gradients
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Depress pacemaker rate Depress conduction & excitability Slows repolarization & lengthens AP duration
→ due to K+ channel blockade with reduction of repolarizing outward current → reduce maximum reentry frequency → slows tachycardia
(+) alpha adrenergic blocking properties → vasodilatation & reflex ↑ SA node rate
CLASS I: Sodium Channel Blocking Drugs
CLASS IA: QUINIDINE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
CLASS I: SODIUM CHANNEL BLOCKERS
Pharmacokinetics:– Oral → rapid GI absorption – 80% plasma protein binding – 20% excreted unchanged in the urine →
enhanced by acidity– t½ = 6 hours– Parenteral → hypotension
Dosage: 0.2 to 0.6 gm 2-4X a day
CLASS IA: QUINIDINE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
CLASS I: SODIUM CHANNEL BLOCKERS
Therapeutic Uses:– Atrial flutter & fibrillation– Ventricular tachycardia– IV treatment of malaria
Drug Interaction:– Increases digoxin plasma levels
CLASS IA: QUINIDINE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
CLASS I: SODIUM CHANNEL BLOCKERS
Toxicity:– Antimuscarinic actions → inh. vagal effects– Quinidine syncope (lightheadedness, fainting)– Ppt. arrhythmia or asystole– Depress contractility & ↓ BP– Widening QRS duration– Diarrhea, nausea, vomiting– Cinchonism (HA, dizziness, tinnitus)– Rare: rashes, fever, hepatitis, thrombocytopenia,etc
CLASS IA: QUINIDINE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Less effective in suppressing abnormal ectopic pacemaker activity
More effective Na+ channel blockers in depolarized cells
Less prominent antimuscarinic action
(+) ganglionic blocking properties → ↓PVR → hypotension (severe if rapid IV or with severe LV dysfunction)
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IA: PROCAINAMIDE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
PHARMACOKINETICS:
Oral, IV, IM N-acetylprocainamide (NAPA) → major
metabolite Metabolism: hepatic Elimination: renal t½ = 3 to 4 hrs.
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IA: PROCAINAMIDE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Dosage:
Loading IV – 12 mg/kg at 0.3 mg/kg/min or less rapidly
Maintenance – 2 to 5 mg/min
Therapeutic Use:
2nd DOC in most CCU for the treatment of sustained ventricular arrhythmias asstd. with MI
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IA: PROCAINAMIDE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Toxicity:
- ppt. new arrhythmias- LE-like syndrome- pleuritis, pericarditis, parenchymal pulmonary disease- ↑ ANA- nausea, DHA, rash, fever, hepatitis, agranulocytosis
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IA: PROCAINAMIDE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
More marked cardiac antimuscarinic effects than quinidine → slows AV conduction
Pharmacokinetics:
- oral administration
- extensive protein binding
- t½ = 6 to 8 hrs
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IA: DISOPYRAMIDE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Dosage: 150 mg TID up to 1 gm/day Therapeutic Use: Ventricular arrhythmias Toxicity:
- negative inotropic action (HF without prior myocardial dysfunction)
- Urinary retention, dry mouth, blurred vision, constipation, worsening glaucoma
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IA: DISOPYRAMIDE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Approved only in serious ventricular arrhythmias Broad spectrum of action on the Very effective Na+ channel blocker but low affinity
for activated channels Markedly lengthens AP by blocking also K+
channels Weak Ca++ channel blocker Noncompetetive inhibitor of beta adrenoceptors Powerful inhibitor of abnormal automaticity
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IA: AMIODARONE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Slows sinus rate & AV conduction Markedly prolongs the QT interval Prolongs QRS duration ↑ atrial, AV nodal & ventricular refractory
periods Antianginal effects – due to noncompetetive α
& β blocking property and block Ca++ influx in vascular sm.m.
Perivascular dilatation - α blocking property and Ca++ channel-inhibiting effects
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IA: AMIODARONE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Pharmacokinetics:
> t½ = 13 to 103 days
> effective plasma conc: 1-2 μg/ml Dosage: - Loading – 0.8 to 1.2 g daily
- Maintenance – 200 to 400 mg daily Drug Interaction: reduce clearance of warfarin,
theophylline, quinidine, procainamide, flecainide Therapeutic Use: Supraventricular & Ventricular
arrhythmias
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IA: AMIODARONE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Toxicity:- fatal pulmonary fibrosis- yellowish-brown microcrystals corneal deposits- photodermatitis- grayish blue discoloration- paresthesias, tremor, ataxia & headaches- hypo - / hyperthyroidism- Symptomatic bradycardia or heart block- Ppt. heart failure- Constipation, hepatocellular necrosis, inflam’n, fibrosis, hypotension
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IA: AMIODARONE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Intravenous route only Arrhythmias asstd with MI Potent abnormal cardiac activity suppressor Rapidly act exclusively on Na+ channels Shorten AP, prolonged diastole → extends time
available for recovery Suppresses electrical activity of DEPOLARIZED,
ARRHYTHMOGENIC tissues only
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IB: LIDOCAINE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Pharmacokinetics:- Extensive first-pass hepatic metabolism- t½ = 1 to 2 hrs
Dosages: loading- 150 to 200 mgmaintenance- 2-4 mg
Drug Interaction: propranolol, cimetidine – reduce clearance
Therapeutic Use:DOC for suppression of recurrences of
ventricular tachycardia & fibrillation in the first few days after AMI.
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IB: LIDOCAINE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Toxicity:– Ppt. SA nodal standstill or worsen impaired
conduction– Exacerbates ventricular arrhythmias– Hypotension in HF– Neurologic: paresthesias, tremor, nausea,
lightheadedness, hearing disturbances, slurred speech, convulsions
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IB: LIDOCAINE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Congeners of lidocaine Oral route - resistant to first-pass hepatic
metabolism Tptic use: ventricular arrhythmias Elimination t½ = 8 to 20 hrs Dosage: Mexiletene – 600 to 1200 mg/day
Tocainide – 800 to 2400 mg/day S/E: tremors, blurred vision, lethargy, nausea,
rash, fever, agranulocytosis
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IB: TOCAINIDE & MEXILETENE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Anti-convulsant with anti-arrhythmic properties Suppresses ectopic pacemaker activity Useful in digitalis-induced arrhythmia Extensive, saturable first-pass hepatic metabolism Highly protein bound Toxicity: ataxia, nystagmus, mental confusion,
serious dermatological & BM reactions, hypotension, gingival hyperplasia
D/I: Quinidine, Mexiletene, Digitoxin, Estrogen, Theophyllin, Vitamin D
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IB: PHENYTOIN
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Potent blocker of Na+ & K+ channels No antimuscarinic effects Used in patients with supraventricular
arrhythmias Effective in PVC’s Hepatic metabolism & renal elimination Dosage: 100 to 200 mg bid
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IC: FLECAINIDE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
(+) weak β-blocking activity Potency ≈ flecainide Average elim. t½ = 5 to 7 hrs. Dosage: 450 – 900 mg TID Tptic use: supraventricular arrhythmias Adv. effects: metallic taste, constipation,
arrhythmia exacerbation
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IC: PROPAFENONE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Antiarrhythmic phenothiazine derivative Used in ventricular arrhythmias Potent Na+ channel blocker Donot prolong AP duration Dosage: 200 to 300 mg orally tid Adv. effects: dizziness, nausea
CLASS I: SODIUM CHANNEL BLOCKERS
CLASS IC: MORICIZINE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
↑ AV nodal conduction time (↑ PR interval) Prolong AV nodal refractoriness
– Useful in terminating reentrant arrhythmias that involve the AV node & in controlling ventricular response in AF & A.fib.
Depresses phase 4 → slows recovery of cells, slows conduction & decrease automaticity
Reduces HR, decrease IC Ca2+ overload & inhibit after depolarization automaticity
Prevent recurrent infarction & sudden death in patients recovering from AMI
CLASS II: BETA ADRENOCEPTOR BLOCKERS
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
“membrane stabilizing effect” Exert Na+ channel blocking effect at high doses Acebutolol, metoprolol, propranolol, labetalol,
pindolol
“intrinsic sympathetic activity” Less antiarrhythmic effect Acebutolol, celiprolol, carteolol, labetalol, pindolol
Therapeutic indications: Supraventricular & ventricular arrhythmias hypertension
CLASS II: BETA ADRENOCEPTOR BLOCKERS
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Propranolol – (+) MSA Acebutolol – as effective as quinidine in
suppressing ventricular ectopic beats
Esmolol - short acting hence used primarily for intra-operative & other acute arrhythmias
Sotalol – has K+ channel blocking actions (class III)
CLASS II: BETA ADRENOCEPTOR BLOCKERS
Specific agents:
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Drugs that prolong effective refractory period by prolonging action potential
Prolong AP by blocking K+ channels in cardiac muscle (↑ inward current through Na+ & Ca++ channels)
Quinidine & Amiodarone → prolong AP duration Bretylium & Sotalol → prolong AP duration &
refractory period Ibutilide & Dofetilide → “pure” class III agents Reverse use-dependence
CLASS III: POTASSIUM CHANNEL BLOCKERS
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Antihypertensive Interferes with neuronal release of
catecholamines With direct antiarrhythmic properties Lengthens ventricular AP duration & effective
refractory period Markedly ↑ strength of electrical stimulation
needed to induce V.fib. & delays onset of fibrillation after acute coronary ligation
(+) inotropic action
CLASS III: POTASSIUM CHANNEL BLOCKERS
BRETYLIUM
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Intravenous administration Dosage: 5 mg/kg Tptic Use: ventricular fibrillation In emergency setting, during attempted
resuscitation from ventricular fibrillation when lidocaine & cardioversion have failed
S/E: postural hypotension***ppt. ventricular arrhythmianausea & vomiting
CLASS III: POTASSIUM CHANNEL BLOCKERS
BRETYLIUM
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Nonselective beta-blocker that also slows repolarization & prolongs AP duration
Effective antiarrhythmic agent Used in supraventricular & ventricular
arrhythmias in pediatric age group Renal excretion Dosage: 80 – 320 mg bid Toxicity: torsades de pointes
beta-blockade symptoms
CLASS III: POTASSIUM CHANNEL BLOCKERS
SOTALOL
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Slows repolarization Prolong cardiac action potentials MOA: > enhance inward Na+ current
> by blocking Ikr-
> both routes: Oral, IV (1 mg over 10min) Clin. Uses: atrial flutter, atrial fibrillation Toxicity: Torsades de pointes
CLASS III: POTASSIUM CHANNEL BLOCKERS
IBUTILIDE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
A potential Ikr- blocker
Dosage: 250-500 ug bid Clin. Uses: Atrial flutter & fibrillation Renal excretion Toxicity: Torsade de pointes
CLASS III: POTASSIUM CHANNEL BLOCKERS
DOFETILIDE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Blocks both activated & inactivated calcium channels
Prolongs AV nodal conduction & effective refractory period
Suppress both early & delayed afterdepolarizations
May antagonize slow responses in severely depolarized tissues
Peripheral vasodilatation → HPN & vasospastic disorders
CLASS IV: CALCIUM CHANNEL BLOCKERS
VERAPAMIL
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Oral administration → 20% bioavailability t½ = 7 hrs Liver metabolism Dosage:
IV: 5-10 mg every 4-6 hrs or infusion of 0.4 ug/kg/minOral: 120-640 mg daily, divided in 3-4 doses
Tptic use: SVT, AF, atrial fib, ventricular arrhythmias Toxicity: AV block, can ppt. sinus arrest
constipation, lassitude, nervousness, peripheral edema
CLASS IV: CALCIUM CHANNEL BLOCKERS
VERAPAMIL
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Similar efficacy to verapamil in supraventricular arrhythmias & rate control in atrial fibrillation
Bepridil AP & QT prolonging action→ ventricular
arrhythmias but may ppt. torsade de pointes Rarely used → primarily to control refractory
angina
CLASS IV: CALCIUM CHANNEL BLOCKERS
DILTIAZEM & BEPRIDIL
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Indirectly alters autonomic outflow by increasing parasympathetic tone & decreasing sympathetic tone
Results in decreased conduction time & increased refractory period in the AV node
MISCELLANEOUS ANTIARRHYTHMIC AGENTS:
DIGITALIS
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
A nucleoside that occurs naturally in the body t½ ≈ 10 seconds MOA: enhances K+ conductance & inhibits
cAMP-induced Ca++ influx → results in marked hyperpolarization & suppression of Ca++-dependent AP
IV bolus: directly inhibits AV nodal conduction & ↑ AV nodal refractory period
MISCELLANEOUS ANTIARRHYTHMIC AGENTS:
ADENOSINE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
DOC for prompt conversion of paroxysmal SVT to sinus rhythm due to its high efficacy & very short duration of action
Dosage: 6-12 mg IV bolus D/I:
theophylline, caffeine – adenosine receptor blockers
Dipyridamole – adenosine uptake inhibitor Toxicity: flushing, SOB or chest burning, atrial
fibrillation, headache, hypotension, nausea, paresthesia
MISCELLANEOUS ANTIARRHYTHMIC AGENTS:
ADENOSINE
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Effective in patients with recurrent episodes of torsades de pointes (MgSO4 1 to 2 g IV) & in digitalis-induced arrhythmia
MOA: unknown → influence Na+/K+ ATPase, Na+ channels, certain K+ and Ca++ channels
MISCELLANEOUS ANTIARRHYTHMIC AGENTS:
MAGNESIUM
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
Therapy directed toward normalizing K+ gradients & pools in the body
Effects of increasing serum K+:1. resting potential depolarizing action2. membrane potential stabilizing action
Hypokalemia: ↑ risk of early & delayed afterdepolarization ↑ ectopic pacemaker activity esp if (+) digitalis
Hyperkalemia: Depression of ectopic pacemakers Slowing of conduction
ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS
MISCELLANEOUS ANTIARRHYTHMIC AGENTS:
POTASSIUM