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SA node
ATRIA
AV node His-Purkinje System VENTRICLES
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
Phase 0 >Rapid depolarization >Opening fast Na+ channels Na+ rushes in depolarization
MECHANISMS OF ARRHYTHMIA
ARRHYTHMIA DYSRRHYTHMIA absence of rhythm abnormal rhythm
2. Disturbance in Impulse Conduction Block results from severely depressed conduction Re-entry or circus movement / daughter impulse
1. Ischemia
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
ARRHYTHMIAS: Ventricular: Supraventricular: - Wolff-Parkinson- Atrial Tachycardia White (preexcitation - Paroxysmal Tachycardia - Multifocal Atrial Tachycardia - Atrial Fibrillation - Atrial Flutter
syndrome)
-
IA
IB
IC
lengthen AP duration Intermediate interaction with Na+ channels Quinidine, Procainamide, Disopyramide shorten AP duration rapid interaction with Na+ channels Lidocaine, Mexiletene, Tocainide, Phenytoin no effect or minimal AP duration slow interaction with Na+ channels Flecainide, Propafenone, Moricizine
Increase AV nodal conduction Increase PR interval Prolong AV refractoriness Reduce adrenergic activity Propranolol, Esmolol, Metoprolol, Sotalol
Prolong effective refractory period by prolonging Action Potential Amiodarone - Ibutilide Bretylium - Dofetilide Sotalol
Miscellaneous:
ADENOSINE
inhibits AV conduction & increases AV refractory period Indirectly alters autonomic outflow Na+/K+ ATPase, Na+, K+, Ca++ channels normalize K+ gradients
DIGITALIS MAGNESIUM
POTASSIUM
QUINIDINE
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
Pharmacokinetics: Oral rapid GI absorption 80% plasma protein binding 20% excreted unchanged in the urine enhanced by acidity t = 6 hours Parenteral hypotension Dosage: 0.2 to 0.6 gm 2-4X a day
Therapeutic Uses: Atrial flutter & fibrillation Ventricular tachycardia IV treatment of malaria Drug Interaction: Increases digoxin plasma levels
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
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)
PHARMACOKINETICS:
Oral, IV, IM N-acetylprocainamide (NAPA) major metabolite Metabolism: hepatic Elimination: renal t = 3 to 4 hrs.
Therapeutic Use: 2nd DOC in most CCU for the treatment of sustained ventricular arrhythmias asstd. with MI
Toxicity:
- ppt. new arrhythmias - LE-like syndrome - pleuritis, pericarditis, parenchymal pulmonary disease - ANA - nausea, DHA, rash, fever, hepatitis, agranulocytosis
More marked cardiac antimuscarinic effects than quinidine slows AV conduction Pharmacokinetics: - oral administration - extensive protein binding - t = 6 to 8 hrs
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
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
Slows sinus rate & AV conduction Markedly prolongs the QT interval Prolongs QRS duration atrial, AV nodal & ventricular refractory periods Antianginal effects due to noncompetetive & blocking property and block Ca++ influx in vascular sm.m. Perivascular dilatation - blocking property and Ca++ channel-inhibiting effects
Pharmacokinetics: > t = 13 to 103 days > effective plasma conc: 1-2 g/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
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, inflamn, fibrosis,
hypotension
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
Pharmacokinetics: - Extensive first-pass hepatic metabolism - t = 1 to 2 hrs Dosages: loading- 150 to 200 mg maintenance- 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.
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
Congeners of lidocaine Oral route - resistant to first-pass hepatic metabolism Tptic use: ventricular arrhythmias Elimination t = 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
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
Potent blocker of Na+ & K+ channels No antimuscarinic effects Used in patients with supraventricular arrhythmias Effective in PVCs Hepatic metabolism & renal elimination Dosage: 100 to 200 mg bid
(+) weak -blocking activity Potency flecainide Average elim. t = 5 to 7 hrs. Dosage: 450 900 mg TID Tptic use: supraventricular arrhythmias Adv. effects: metallic taste, constipation, arrhythmia exacerbation
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
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
Exert Na+ channel blocking effect at high doses Acebutolol, metoprolol, propranolol, labetalol, pindolol Less antiarrhythmic effect Acebutolol, celiprolol, carteolol, labetalol, pindolol Supraventricular & ventricular arrhythmias hypertension
Therapeutic indications:
Specific agents:
Propranolol Acebutolol
Esmolol
Sotalol
(+) MSA as effective as quinidine in suppressing ventricular ectopic beats - short acting hence used primarily for intra-operative & other acute arrhythmias has K+ channel blocking actions (class III)
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
BRETYLIUM 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
BRETYLIUM 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 arrhythmia nausea & vomiting
SOTALOL
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
IBUTILIDE
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
DOFETILIDE
A potential Ikr- blocker Dosage: 250-500 ug bid Clin. Uses: Atrial flutter & fibrillation Renal excretion Toxicity: Torsade de pointes
VERAPAMIL 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
VERAPAMIL
Oral administration 20% bioavailability t = 7 hrs Liver metabolism Dosage: IV: 5-10 mg every 4-6 hrs or infusion of 0.4 ug/kg/min Oral: 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
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
DIGITALIS
Indirectly alters autonomic outflow by increasing parasympathetic tone & decreasing sympathetic tone Results in decreased conduction time & increased refractory period in the AV node
ADENOSINE
A nucleoside that occurs naturally in the body t 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
ADENOSINE 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
MAGNESIUM
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
POTASSIUM
Therapy directed toward normalizing K+ gradients & pools in the body Effects of increasing serum K+: 1. resting potential depolarizing action 2. membrane potential stabilizing action Hypokalemia: risk of early & delayed afterdepolarization ectopic pacemaker activity esp if (+) digitalis Hyperkalemia: Depression of ectopic pacemakers Slowing of conduction