Pharmacology 31,32 - Arrhythmias & Antiarrhythmic Agents I&ii

Front 1

Name the Class I drugs and where they act?

Back 1

IA-Quinidine
IB-Lidocaine
IC-Flecainide

Na+ channel blockers

Front 2

Name the Class II drugs and where they act?

Back 2

Propranolol

Beta blockers

Front 3

Name the Class III drugs and where they act?

Back 3

Amiodarone
Sotalol

Prolong repolarization (K+ channel bl.)

Front 4

Name the Class IV drugs and where they act?

Back 4

Verapamil

Ca2+ channel blockers

Front 5

Name the Miscellaneous drugs and where they act?

Back 5

Adenosine
Digoxin
Magnesium
Potassium

Front 6

What are the phases of generating an action potential?

Back 6

Phase 0 -- opening Na+ channels, rapid depolarization, inactivation Na+ channels; (in SA and AV node, the 0 Phase is Ca++ current dependent (slow response)
Phase 1 -- rapid partial repolarization due to the inactivation of fast sodium channels
Phase 2 -- plateau phase, Ca2+ channels are open
Phase 3 -- repolarization,Ca2+ channels inactivated, K+ channels open, Na+ channels turning to rested state
Phase 4 -- resting membrane potential, spontaneous depolarization

Front 7

What is the Goal of arrhythmia therapy?

Back 7

-Reduce ectopic pacemaker activity
-Modify conduction or refractoriness to disable reentry

Front 8

What are some mechanisms of Therapy?

Back 8

-sodium channel blockade
-blockade of sympathetic effects
-prolongation of the effective refractory period
-calcium channel blockade

Front 9

What are the main features of antiarrhythmic drugs?

Back 9

decrease automaticity of ectopic pacemakers more than that of the SA node
• reduce conduction and excitability and increase the refractory period to a greater extent in depolarized tissue than in normally polarized tissues
• accomplished by selectively blocking the sodium and calcium channels of depolarized cells
• have high affinity for activated or inactivated but low affinity for rested channels (use-dependent or state dependent action)
• in cells with abnormal automaticity these drugs reduce phase 4 depolarization
• beta blockers remove the chronotropic action of norepinephrine (NE)

Front 10

What is the prototype of Class IA agents? Describe it?

Back 10

Quinidine (Cardioquin)
• Quinidine is the d-isomer of quinine and has been in clinical use for over sixty years.
• Quinidine is a prototype of Class 1 antiarrhythmic Drugs

Front 11

What is the MOA of Quinidine?

Back 11

binding to open and activated sodium channels (“state dependent” blockade)
o decreasing the myocardial automaticity and membrane responsiveness
o increasing the diastolic threshold
o slowing maximal rate of rise of the cellular action potential (Vmax of 0 phase)
o prolonging the Action Potential Duration (APD) Prolonging the Effective Refractory Period (ERP)
increasing the ratio of ERP/ADP and preventing the closely coupled "re-entry circuit" in the Purkinje fibers
o blocking K+ channels (prolongs depolarization)

Front 12

What are the other Cardiac Effects of Quinidine?

Back 12

o Quinidine causes muscarinic receptor blockade, which can increase HR and AV conduction
o Quinidine causes certain EKG changes - such as widening of QRS and QT intervals, etc. These are the manifestations of toxicity
o Quinidine causes S-A block, A-V block, ventricular, arrhythmia, and severe hypotension at toxic doses.

Front 13

What are some other effects of Quinidine?

Back 13

o blocks alpha receptors (hypotension), may cause reflex tachycardia
o G.I. irritation, nausea, vomiting and diarrhea
o CNS stimulation, convulsions at very high doses
o "Cinchonism", tinnitus, headache, vertigo, allergy.
o Quinidine has a curare-like effect (membrane stabilizing effect) on the skeletal muscle
o Quinidine potentiates the action of neuromuscular blocking agents

Front 14

What is the pharmacokinetics of Quinidine?

Back 14

• oral administration is most common, relatively safe and rapid in onset
• absorption is essentially complete
• bioavailability is variable due to "first pass" effect
• I.V. administration is hazardous (causes severe hypotension), I.M. injection is painful
• maximal blood levels are reached in 90 minutes
• about 80% of the drug is metabolized by the liver, 20% is excreted through the kidney
• t1/2 is about 6 hours. The t1/2 is prolonged in congestive heart failure or in renal insufficiency
• 70%-80% quinidine is plasma protein bound
• a major metabolite of quinidine is also active

Front 15

What Toxicity is associated with Quinidine?

Back 15

• quinidine is a potentially dangerous drug with a low therapeutic index.
• cardiac toxicity is the most significant, often life threatening.
• quinidine causes severe hypotension and shock-like effect by virtue of its alpha-adrenergic receptor blocking action.
• paradoxical tachycardia ("anticholinergic" effect)
• quinidine syncope and death: This occurs mostly in those patients receiving digitalis and quinidine together. Patients with long QT interval are at great risk.
• torsade de pointes
• diarrhea, nausea and vomiting is the most often seen extracardiac toxicity
• Cinchonism: Loss of hearing, angioedema, vertigo, tinnitus, visual disturbances, thrombocytopenic purpura, vascular collapse.

Front 16

What are some CI's for Quinidine?

Back 16

• Pre-existing complete A-V block (ventricular arrest may take place).
• Thrombocytopenia associated with previous quinidine therapy (allergic response).

Front 17

What is the Therapeutic use for Quinidine?

Back 17

Quinidine is a "broad spectrum" antiarrhythmic drug effective for acute or chronic treatment of varieties of supraventricular and ventricular arrhythmias.

Front 18

Does Quinidine have any drug interactions?

Back 18

• Drugs like phenytoin and phenobarbital which induce hepatic microsomal enzymes are likely to shorten the duration of action of quinidine action by increasing its metabolism
• quinidine may increase prothrombin time in patients receiving oral anticoagulant warfarin therapy
• quinidine and nitroglycerin will produce a significant vasodilation and fall in blood pressure
• increased plasma K+ may enhance the toxic effect of quinidine
• quinidine may exaggerate skeletal muscle weakness, or increase the paralyzing effect of curare and curare-like drugs, aminoglycosides

Front 19

What is Procainamide? How does it work?

Back 19

• electrophysiological and pharmacological actions similar to those of quinidine
• short duration of action
• high incidence of adverse reactions upon chronic use
• can be administered safely I.V.
• procainamide may be useful in patients with severe ventricular arrhythmias who are unresponsive to lidocaine
MOA is similar to Quinidine.

Front 20

What are the pharmacokinetics of Procainamide?

Back 20

• well absorbed after oral administration
• bioavailability 75%
• peak plasma levels: 15-60 minutes
• protein binding: 20%
• half-life: 3-5 hours
• t1/2 is prolonged in renal insufficiency, hepatic disease and congestive heart failure
• metabolism: acetylated to active n-acetyl procainamide (NAPA) in the liver
• the rate of acetylation is under genetic control and shows bimodal distribution into "slow" and "fast" acetylators; fast acetylators have higher plasma ratio of NAPA/ procainamide
• about 40-60% is excreted in the urine

Front 21

Does Procainamide have any Toxicity?

Back 21

• in general, adverse effects of procainamide are almost similar to those of quinidine, including precipitation of new arrhythmias, torsade de pointes
• anorexia, nausea, and vomiting (but procainamide is better tolerated than quinidine in some patients)
• Systemic Lupus Erythematosus-like Syndrome (SLE) in about 30% of patients during prolonged use
• procainamide causes an increased titer in antinuclear antibodies (ANA) in about 30% of patients
• occasional hypersensitivity (rash, urticaria, fever, agranulocytosis, pancytopenia) may be seen
• rarely, mental disturbances (depression, hallucination, psychosis)

Front 22

What are the precautions and CI's for Procainamide?

Back 22

• Do not use procainamide in complete A-V block
• Use it with great caution in partial A-V block

Front 23

What is the Therapeutic use of Procainamide?

Back 23

• To treat a wide variety of cardiac arrhythmias such as:
o Ventricular arrhythmias -except those resulting from digitalis intoxication
o Supraventricular arrhythmias - atrial flutter and atrial fibrillation, etc.

Front 24

What is Disopyramide?

Back 24

• Disopyramide is structurally unrelated to other commonly used anti-arrhythmic agents like quinidine and procainamide.
• Disopyramide is likely to reduce cardiac index.
• Disopyramide is effective in the management of unifocal, multifocal and paired premature ventricular contractions as well as the episodes of ventricular tachycardia

Front 25

What is Disopyramide's MOA?

Back 25

• mechanism of action of disopyramide is comparable to quinidine i.e., Na+ channel blockade
• prolongs the Effective Refractory Period (ERP), increases the electric threshold, depresses the conduction velocity
• high doses of disopyramide may depress myocardial contractility

Front 26

What are the Pharmacokinetics of Disopyramide?

Back 26

• administered orally, no significant adverse hemodynamic effects following oral administration
• about 16% is metabolized on the "first pass" through the liver
• peak effect 2-4 hours
• plasma half-life 6-8 hours, markedly increased in patients with renal insufficiency
• 80% is excreted in the kidney in 72 hours (45% as unchanged drug)
• 40% protein binding

Front 27

What toxicity is associated with Disopyramide?

Back 27

• prolongation of QT-interval and prominent U waves
• widening of QRS complex, increased P-wave duration
• do not use disopyramide in sick sinus syndrome
• ventricular arrhythmias, including torsade de pointes and syncope
• increases His-Purkinje conduction time but does not affect A-V conduction time
• significant negative inotropic effect, aggravates heart failure
• anticholinergic effects: dry mouth, urinary hesitancy, constipation, blurred vision, contraindicated in glaucoma
• nausea, vomiting, abdominal pain, headache, edema, weight gain, dizziness and fatigue

Front 28

What is Disopyramide used for?

Back 28

Ventricular tachycardia

Front 29

What is the Class IB prototype Drug?

Back 29

Lidocaine (Xylocaine)

• local anesthetic antiarrhythmic agent, prototype for IB
• the use of Lidocaine is limited to the treatment of arrhythmias of ventricular origin

Front 30

What is Lidocaine's MOA?

Back 30

• binds to the inactivated sodium channels, fast binding and dissociation
• decreases APD, shortens ERP due to block of the slow Na+ “window” currents

Front 31

What are the effects of Lidocaine?

Back 31

• lidocaine has no significant effects on QRS, QT intervals
• it causes less hypotension than procainamide
• It has little or no depressant action on myocardial contractility
• it has no vagal blocking action like that of quinidine, procainamide or disopyramide
• antiarrhythmic action develops immediately after I.V. loading dose and declines rapidly upon discontinuation of infusion.
• lidocaine is relatively free of hemodynamic and cardiac complications
• cannot be used orally (first pass metabolism), therefore, is not suitable for maintenance or in an outpatient setting
• lidocaine is not effective for supraventricular arrhythmias

Front 32

What are the Pharmacokinetics of Lidocaine?

Back 32

• I.V. only
• I.V. - loading dose (bolus) is 50 mg - 100 mg (1 mg/kg) at a rate of 25-30 mg/minute. Boluses of above strength may be given every 3-5 minutes until the desired effect is achieved or side effects appear. To maintain anti-arrhythmic effect, I.V. infusion must be maintained at a rate of 1-4 mg/minute
• onset of action – 1-2 minute
• duration of anti-arrhythmic effect – 0-20 minutes
• serum t½ - 8-9 minutes (initial active phase of distribution). To maintain serum levels achieved by the bolus, start I.V. infusion within 10 minutes
• t½ of second phase - 1.5 - 2 hours
• metabolism - primarily in the liver. (90-95%)
• excretion - Less than 5% unchanged drug in the urine
• therapeutic level – 1-5 mg/ml, toxic level – 6-10 mg/mg

Front 33

What toxicities are associated with Lidocaine?

Back 33

• minor side effects are lightheadedness, tinnitus, muscle twitches, blurred double vision
• CNS depression, stupor, restlessness, euphoria, hypotension, and convulsion
• infrequently bradycardia and aggravation of arrhythmia may occur
• very large doses may depress myocardial contractility and A-V conduction (least negative inotropic among the antiarrhythmics)
• Untoward effects are seen mostly in patients with hepatic disease and congestive heart failure, etc.

Front 34

What is Lidocaine used for?

Back 34

ventricular arrhythmias