Title: Pharmacology CVS / Antiarrythmic Drugs

Q: Types of cardiac arrythmias: (2)
A: 1. Abnormalities of impulse formation
2. Abnormalities of impulse conduction

Q: Abnormalities of impulse formation: (2)
A: 1. Rate disturbances
2. Triggered automaticity

Q: Abnormalities of impulse condunction: (2)
A: 1. Blocks
2. Re-entry

Q: Cardiac causes of arrythmias: (5)
A: 1. Ischemic heart disease
2. Inflammation
3. Trauma (such as heart surgery)
4. Congestive heart failure
5. Hypotension

Q: Non-cardiac causes of arrythmias: (5)
A: 1. Electrolyte imbalance
2. Acid-base imbalance
3. Hypoxia
4. Drugs
5. Reflexes

Q: Drugs that cause arrythmias: (5)
A: 1. Digitalis
2. Anesthetics
3. Tricyclic
4. Diuretics
5. Bronchodilators: sympathomemetic

Q: Cardiac
cells undergo depolarization and repolarization to initiate cardiac action
potentials:
A: 60 times per minute

Q: The
shape and duration of each action potential are determined by :
A: The
activity of ion
channel protein complexes
in the membranes of individual cells.

Q: Ion
channel function (that create abnormalities of cardiac rhythm or arrythmias) can be disrupted by: (4)
A: 1. Inherites mutation/polymorphism
2. Acute ischemia
3. Sympathetic stimulation
4. Myocardial scarring

Q: Pre-requisites for
Reentry (Circus Movement): (3)
A: 1. Anatomic or physiologic obstacle
2. Unidirectional block
3. Conduction time around the circuit must be longer than the effective refractory period.

Q: Symptoms of Torsades de Pointes (Polymorphic Ventricular Tachycardia): (3)
A: 1. LQT (long QT)
2. Syncope (fainting, passing out)
3. Sudden death

Q: Causes of Torsades de Pointes (Polymorphic Ventricular Tachycardia): (3)
A: 1. Familial long QT interval
2. Drug-induced (drugs which prolong APD [action potential duration]
3. Genetic mutations (300 different mutations in at least 8 ion channel genes)

Q: Mechanisms of Torsades de Pointes (Polymorphic Ventricular Tachycardia): (2)
A: 1. Increased inward current (GF)
2. Decreased outward current (LF) during the plateau

Q: Risk factors of Torsades de Pointes (Polymorphic Ventricular Tachycardia): (4)
A: 1. Bradycardia
2. Hypokalemia
3. Triggered upstrokes
4. Drugs that increase APD

Q: Treatment of Torsades de Pointes (Polymorphic Ventricular Tachycardia): (3)
A: 1. Potassium ions (K+)
2. Decreasing triggered upstrokes (β blockers or Mg++)
3. Decreasing APD (pacemaker or isoproterenol)

Q: Other congenital arrhythmias: (5)
A: 1. Short QT Syndrome
2. Chatecholaminergic Pholymorphic Ventricular Tachycardia (CPVT)
3. Sick Sinus Syndrome
4. Brugada Syndrome
5. Familial Atrial Fibrillation

Q: Short QT Syndrome
A: GF  mutations in three potassium channel genes(KCNH2, KCNQ1, and KCNJ2).

Q: Chatecholaminergic Polymorphic Ventricular Tachycardia (CPVT): (3)
A: 1. Stress or emotion induced syncope
2. caused by mutations in sarcoplasmic proteins that control calcium
3. Inhibiting RyR2 channels with flecainide appears to prevent CPVT.

Q: Sick Sinus Syndrome:
A: Mutations in HCN4 and SCN5A

Q: Brugada Syndrome: (2)
A: 1. Ventricular fibrillation, persistent ST (sinus tachycardia) elevation, and BBB (5 in 10,000).
2. Linked to LF mutations in SCN5A

Q: Familial Artiral Fibrillation:
A: Linked to GF mutation in the potassium channel gene, KCNQ1.

Q: Nonpharmalogical therapy for arrythmias: (5)
A: 1. Surgery
2. Radiofrequency Catheter Ablation
3. Cryoabaltion (freeze and destroy abnormal tissue)
4. Implantable Cardioverter- Defibrillator (ICD)
5. Gene therapy

Q: Available
anti-arrhythmic drugs suppress arrhythmias by:
A: Blocking flow through specific ion channels or by altering autonomic function.

Q: Anti-arrhythmic
drug therapy can have two goals:
A: 1. Termination of an ongoing arrhythmia
2. Prevention of an arrhythmia

Q: Principles of mechanisms of action of antiarrhythmic drugs: (3)
A: 1. Readily bind to activated channels or inactivated channels, but  bind poorly to rested channels.
2. Channels in normal cells  will rapidly lose the drug from the receptors during the resting portion of the cycle.
3. This selectivity is lost with increasing doses, leading to drug-induced arrhythmias.

Q: Antiarrhythmic drugs become proarrhythmic, arrhythmogenic during: (4)
A: 1. Fast heart rates
2. Acidosis
3. Hyperkalemia
4. Ischemia

Q: Class 1A Drugs: (3)
A: 1. Quinidine
2. Procainamide
3. Disopyramide

Q: Quinidine: (5)
A: 1. Prototype, related to quinine.
2. Cinchona tree --> Antipyretic --> Quinine =  Antimalarial.
3. Inhibits a and muscarinic receptors.
4. Slows upstroke, conduction, and prolongs APD and QRS duration.
5. restricted nowadays to pateints with normal hearts (no failure, no ischemia), but have atrial or ventricular arrhythmias.

Q: Side effects of Quinidine: (10)
A: 1. Nausea (18%)
2. Diarrhea (33%).
3. Headache, Dizziness, and tinnitus= Cinchonism
4. Hypersensitivity, fever, rash, angioedema.
5. Thrombocytopenia.
6. Excessive prolongation of QT interval, slowed conduction.
7. Hypotension.
8. Increased serum Digoxin levels.
9. Increased Warfarin effects.
10. Sudden death

Q: Procainamide: (3)
A: 1. Oral, but has short t½.
2. L.E. [lupus erythematosus] (30% of patients under treatment for over 6 months)
3. Acetylated ® NAPA (Class III) action

Q: Class 1B drugs: (4)
A: 1. Lidocaine
2. Tocainide
3. Mexiletine
4. Phenytoin

Q: Lidocaine (Lignocaine, or Xylcaine): (4)
A: 1. High affinity to bind with activated and inactivated Na+ channels with rapid kinetics.
2. Acts selectively in ischemic ventricular tissue to promote conduction and block reentry.
3. More effective with  K+.
4. Not effective in atrial arrhythmias.

Q: Kinetics of Lidocaine: (2)
A: 1. Well absorbed, but ineffective orally, due to first   pass effect, so given IV.
2. Well distributed, including the brain.

Q: Side effects of Lidocaine: (3)
A: 1. Least cardiotoxic of the class, except for   hypotension with high doses due to depression of the myocardium.
2. CNS: paresthesia, tremor, nausea, slurred   speech, and convulsions.
3. Was routinely given to all MI patients to    prevent ventricular arrhythmias.

Q: Tocainide: (2)
A: 1. Oral analog of lidocaine.
2. CNS, GI and blood dyscrasia.

Q: Mexiletine: (2)
A: 1. Oral analog of lidocaine.
2. Neurologic side effects.

Q: Phenytoin: (4)
A: 1. Antiepileptic.
2. For Digitalis- induced arrhythmias.
3. For arrhythmias after congenital heart surgery.
4. Also for Congenital prolonged QT interval.

Q: Class 1C drugs: (2)
A: 1. Felcainide
2. Propafenone

Q: Felcainide: (4)
A: 1. Potent blocker of Na + and K+ channels.
2. Negative inotropic effect.
3. Proarrhythmic --> ventricular.
4. Effective in supra ventricular   tachycardia with normal hearts.

Q: Side effects of Felcainide: (3)
A: 1. Ventricular arrhythmias
2. CNS effects
3. Sudden death

Q: Propafenone: (3)
A: 1. Blocks Na+ channels but also has beta blocking and Ca++ blocking activity
2. No effect on QT interval
3. Used for supraventricular arrhythmias

Q: Side effects of Propafenone: (3)
A: 1. Metallic taste
2. Constipation
3. Arrhythmias

Q: Class II drugs: (3)
A: 1. Propranolol
2. Esmolol
3. Acebutolol

Q: Propranolol: (2)
A: 1. Besides beta blocking, membrane stabilization, and intrinsic sympathomimetic activities, has effective antiarrhythmic activity
2. Very effective, well tolerated, and documented to reduce mortality after acute myocardial infarction by reducing arrhythmias, besides reducing myocardial oxygen requirements.

Q: Esmolol and Acebutolol: (2)
A: 1. β1 selective drugs.
2. Short acting, used in intraoperative and acute arrhythmias

Q: Class III drugs: (5)
A: 1. Amiodarone
2. Bretylium Tosylate
3. Sotalol
4. Ibutilide
5. Dofetilide

Q: Amiodarone: (5)
A: 1. Blocks K+ channels and markedly prolongs APD. Also: Class I actions, blocks a and b Receptors, Ca++ blocking actions.
Effect is due to alteration of  lipid membrane.
2. Reserved for life-threatening atrial and ventricular arrhythmias.
3. Slows heart rate and AV conduction.
4. Low incidence of TdP despite significant QT prolongation.
5. Peripheral vasodilator (only with IV).

Q: Kinetics of Amiodarone: (2)
A: 1. Given IV (Loading dose 10gm) and orally.
2. Slow kinetics (t½ 25-110 days), metabolized by CYP3A4 enzymes.

Q: Toxicity of Amiodarone: (7)
A: 1. Lung fibrosis (1%).
2. CNS.
3. Thyroid (hypo and hyper).
4. GI and liver.
5. Corneal deposits,
6. Skin: photodermatitis and discoloration.
7. Increased toxicity with Digoxin & Anticoagulants.

Q: Bretylium Tosylate: (4)
A: 1. Originally an antihypertensive, but tolerance develops.
2. Releases NE, then decreased release / reuptake
3. Rarely used, except for prevention of ventricular fibrillation after  failure of cardioversion and lidocaine.
4. Hypotension, parotid swelling.

Q: Sotalol: (3)
A: 1. Beta blocker  but has Class III actions.
2. For atrial and ventricular arrhythmias.
3. Causes bradycardia, HF (heart failure), and  prolongation of QT.

Q: Class IV drugs: (Ca++ channel blockers) (2)
A: 1. Verapamil
2. Dilitiazem

Q: Verapamil and Dilitiazem: (4)
A: 1. Block activated and inactivated L-type Ca++ channels.
2. Effects more marked in tissues that fire frequently, less completely polarized at rest, and those dependant on Ca++ (SA node and AV node).
3. Used for Paroxysmal Supraventricular Tachycardia.
4. Vasodilators, and have negative inotropic effects.

Q: Side effects of Verapamil and Dilitiazem: (7)
A: 1. Can cause severe AV block in diseased hearts.
Relatively safe:
2. Constipation
3. Gastric discomfort
4. Vertigo
5. Headache
6. Nervousness
7. Pruritis.

Q: Digoxin: (4)
A: 1. Old fashioned agent for heart failure    and atrial arrhythmias.
2. Direct Actions.
3. Vagotonic Effects.
4. Increased AV refractoriness.

Q: Magnesium: (3)
A: 1. Works on Na+/K+ ATPase, Na+ channels, certain K+ channels and Ca++ channels.
2. Effective IV in refractory digitalis- induced  ventricular arrhythmias only in hypomagnesemic patients.
3. Effective in TdP patients even if serum Mg++ is normal.

Q: Pottasium salts: (2)
A: 1. For digitalis- induced arrhythmias with hypokalemia.
2. Depress ectopic pacemakers and slow conduction.

Q: Adenosine: (9)
A: 1. Naturally occurring nucleoside.
2. Stimulates purinergic (P1) receptors.
3. Activates inward rectifier K+ current and inhibits   Ca++ current.
4. Very short acting (t 1/2 10 seconds).
5. Decreased phase 4 depolarization in SA node.
6. Decreased AV conduction.
7. No effect on ventricles.
8. 90-95% effective in supraventricular tachycardia, replaced verapamil.
9. Less effective in the presence of adenosine receptor blockers, e.g. theophylline  and caffeine.

Q: Side effects of Adenosine: (7)
A: 1. Transient flushing (20%)
2. Chest tightness
3. AV block
4. Headache
5. Hypotension
6. Nausea
7. Parasthesia

Q: Possible effects of drugs on action potential: (4)
A: 1. Decreased phase 4 slope
2. Increased threshold
3. Increased maximum diastolis potential
4. Increased action potential duration

Q: Mechanism of class I antiarrythmic drugs
A: Sodium channel blockers

Q: Difference between mechanism of class I a/b/c antiarrythmic
A: Class Ia: intermediate dissociation
Class Ib: fast dissociation
Class Ic: slow dissociation

Q: Mechanism of class II antiarrythmic drugs:
A: β- adrenoceptor antagonism

Q: Mechanism of class III antiarrythmic drugs:
A: Pottasium channel block

Q: Mechanism of class IV antiarrythmic drugs:
A: Calcium channel blocker

Q: Effect of Class I antiarrhythmic drugs on ventricuar action potential (on the ECG)
Class Ia: [...]
Class Ib: [...]
Class Ic: [...]
A: increased QRS and QT; decreased QT; greatly increased QT