Anti Arrhythmic Agents
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ANTIARRHYTHMICS AGENTS
Definition: Cardiac arrhythmia are deviations from the normal heartbeat pattern. They include abnormalities of impulse formation, such as heart rate , rhythm, or site of impulse origin, and conduction disturbances, which disrupt the normal sequence of atrial and ventricular activation. Four main structures composed of tissue that can generate or conduct electrical impulses comprise the conduction system of the heart. The SA node, in the wall of the right atrium, contains cells that spontaneously initiate an action potential. Serving as the main pacemaker of the heart, the SA node initiates 60-100 beats/mins. Impulse generated by the SA node trigger atrial contraction. 2
Mr. Gaurang Ramani 3.2 ANTIARRHYTHMIC AGENT
3
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Impulses travel through intermodal tracts- the anterior tract, middle tract, posterior tract and anterior internal tract. At the AV node, situated in the lower interatrial septum, the impulses are delayed briefly to permit completion of atrial contraction before ventricular contraction begins. At the bundle of His-muscle fibers arising from the AV junctionimpulses travel along the left and right bundle branches, located on either side of the intraventricular septum. The impulses reach the Purkinje fibers, a diffuse network extending from the bundle branches and ending in the ventricular endocardial surfaces. Ventricular contraction then occurs. 4
Mr. Gaurang Ramani 3.2 ANTIARRHYTHMIC AGENT
Depolarization and repolarization result from changes in the electrical potential across the cell membrane, caused by the exchange of sodium and potassium ions. Action potential, which reflects this electrical activity, has five phases. Phase 0 (rapid depolarization) takes place as sodium ions enter the cell through fast channel; the cell membrane’s electrical charge changes from negative to positive. Phase 1 (early rapid repolarization). As fast sodium channel close and potassium ions leave the cell, the cell rapidly repolarizes (e.g. return to resting potential). Phase 2 (plateau). Calcium ions enter the cell through slow channels while potassium ions exit. As the cell membrane’s electrical activity temporarily stabilizes, the action potential reaches a plateau. 5
Mr. Gaurang Ramani 3.2 ANTIARRHYTHMIC AGENT
Phase 3 (final rapid polarization). Potassium ions are pumped out of the cell as the cell rapidly completes repolatization and resumes its initial negativity. Phase 4 (slow depolrization). The ell returns to its resting state with potassium ions inside the cell and sodium and calcium ions outside.
6
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
7
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Antiarrhythmic agents are a group of pharmaceuticals that are used to suppress fast rhythms of the heart (cardiac arrhythmias), such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation. Class I agents interfere with the sodium (Na+) channel. Class II agents are anti-sympathetic nervous system agents. Most agents in this class are beta blockers. Class III agents affect potassium (K+) efflux. Class IV agents affect calcium channels and the AV node. Class V agents work by other or unknown mechanisms.
8
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Class Ia
Ib
Ic
9
Mr. Gaurang Ramani
Examples •
Quinidine
•
Procainamide
•
Disopyramide
•
Lidocaine
•
Phenytoin
•
Mexiletine
•
Flecainide
•
Propafenone
•
Moricizine
3.2 ANTIARRHYTHMIC AGENT
II
III
IV
V
10
Mr. Gaurang Ramani
•
Propranolol
•
Esmolol
•
Timolol
•
Metoprolol
•
Atenolol
•
Amiodarone
•
Sotalol
•
Ibutilide
•
Dofetilide
•
Verapamil
•
Diltiazem
•
Adenosine
•
Digoxin 3.2 ANTIARRHYTHMIC AGENT
Class I agents The class I antiarrhythmic agents interfere with the sodium channel. Class I agents are grouped by what effect they have on the Na+ channel, and what effect they have on cardiac action potentials. Class 1 agents are called Membrane Stabilizing agents. Class I agents are divided into three groups (1a, 1b and 1c) based upon their effect on the length of the action potential. 1a lengthens the action potential (right shift) 1b shortens the action potential (left shift) 1c does not significantly affect the action potential (no shift) 11
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
12
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
MOA: It reduces the slope of phase 4 depolarization in pacemaker cells. This is probably due to a reduction of diastolic sodium influx. Thus it abolishes ectopic pacemakers activity. It also reduces the transfer of sodium across the cell membrane during phase 0 of the action potential. As a result the conduction velocity is decreased and the refractory period is prolonged. Due to the decreased sodium influx there is decreased efflux of potassium, which has a specific membrane stabilizing effect on the cardiac cell. The reduction in potassium efflux may be responsible for the increase in the duration of the action potential observed with Ia. It blocks open sodium (Na+) channels and prolongs the cardiac action potential. This results in slowed conduction, and ultimately the decreased rate of rise of the action potential.
13 Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Quinidine: 200-300 mg Side effects Thrombocytopenia (low platelet count) Cinchonism (headache, dizziness, hearing loss)with tinnitus (ringing in the ears), nausea, vomiting, diarrhea, confusion.
14
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Procainamide : 500-1000mg Side effects Rash,
Myalgia
(pain
in
muscle)
hypersensitivity
reactions
(fever,
agranulocytosis), Drug-Induced Lupus Erythematosus, and proarrhythmic. Treatment with procainamide can cause antibody production against cellular components, accounting for the systemic lupus erythematosus-like adverse reactions.
15
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Disopyramide: 400-800mg/day Cardiac Adverse Effects Acute heart failure Severe hypotension Extracardiac Effects Dry mouth Constipation Urinary retention Blurred vision Glaucoma Rash Agranulocytosis
16
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Class 1b
Class Ib agents shorten the action potential duration. These agents will decrease Vmax
in partially depolarized cells with fast response action
potentials. They either do not change the action potential duration, or they may decrease the action potential duration. Class Ib drugs tend to be much more specific for voltage gated Na channels than Ia. 17
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Lidocaine : 1-1.5 mg/kg Adverse drug reactions Allergic, tinnitus, tremor, dizziness, blurred vision, seizures, drowsiness, loss of consciousness, respiratory depression and apnea (sleep). Cardiovascular effects include hypotension, cardiac arrest Phenytoin: 300-400mg/day Side-effects Heart block, drowsiness, vertigo, nausea, megaloblastic anemia, leuckopenia, thrombocytopenia. Ataxia (Inability to coordinate voluntary muscle movements), Nystagmus (Involuntary movements of the eyeballs).
Mexiletine: 200-400 mg ADR: Dizziness, Ataxia, Nystagmus, Hypotension, Nausea, Vomiting.
18
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Class 1C
MOA: Class Ic antiarrhythmic agents markedly depress the phase 0 depolarization (decreasing Vmax ). It works by blocking the sodium channel in the heart, causing prolongation of the cardiac action potential. This thereby slows conduction of the electrical impulse within the heart. The greatest effect is on the His-Purkinje system and ventricular myocardium. Of the sodium channel blocking antiarrhythmic agents, the class Ic agents have the most potent sodium channel blocking effects. Class Ic agents are indicated for life-threatening ventricular tachycardia or ventricular fibrillation, and for the treatment of refractory supraventricular tachycardia (ie: atrial fibrillation). 19
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Flecainide: 50-100 mg/12 hrs Serious adverse reactions Dizziness, headache, treamor, nausea, abdominal pain Propafenone: 150 mg/8 hrs Side effects hypersensitivity reactions, lupus-like syndrome, agranulocytopenia, dizziness, lightheadedness (a feeling that you are about to fall), gastrointestinal upset, a metallic taste and bronchospasm.
20
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Class II agents MOA: Parasympathetic (vagal) activation decreases conduction velocity at the AV node by decreasing the slope of phase 0 of the nodal action potentials. This leads to slower depolarization of adjacent cells, and reduced velocity of conduction Class II agents are conventional beta blockers. They act by blocking the effects of catecholamines at the β1-adrenergic receptors, thereby decreasing sympathetic activity on the heart. These agents are particularly useful in the treatment of supraventricular tachycardias. They decrease conduction through the AV node. Propranolol: 10-80 mg/day ADR: fatigue, lethargy, increased airway resistance, skin rashes, nausea, vomiting, diarrhea. 21
Mr. Gaurang Ramani
ESOMOLOL: 50microg/kg/min
3.2 ANTIARRHYTHMIC AGENT
Class III agents MOA: Class III agents predominantly block the potassium channels, thereby prolonging repolarization. Since these agents do not affect the sodium channel, conduction velocity is not decreased. The prolongation of the action potential duration and refractory period, combined with the maintenance of normal conduction velocity, prevent re-entrant arrhythmias. AMIODARONE: 200-600 mg/day ADR:
Fatigue, malaise (mild sickness or depression), peripheral neuropathy,
extrapyramidal effect, nausea, vomiting SOTALOL: 160-480 mg/kg ADR: Bradycardia, myocardial depression, bronchospasm BRETYLIUM: 5mg/kg ADR: Nausea, vomiting 22
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Class IV agents MOA: Phase 0 of action potentials at the AV node is not dependent on fast sodium channels, but instead is generated by the entry of calcium into the cell through slow-inward calcium channels. Blocking these channels with a calcium-channel blocker such as verapamil or diltiazem reduces the conduction velocity of impulses through the AV node and can produce AV block. Class IV agents are slow calcium channel blockers. They decrease conduction through the AV node (Depression). Shorten phase two (the plateau) of the cardiac action potential. Verapamil 5-10 mg & Diltiazem 20 mg ADR: constipation and nausea 23
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Other agents ("Class V") Since the development of the original Vaughan-Williams classification system, additional agents have been used that don't fit cleanly into categories I to IV. Some sources use the term "Class V" However, they are more frequently identified by their precise mechanism. Agents include: Digoxin, which decreases conduction of electrical impulses through the AV node and increases vagal activity via its central action on the central nervous system. Adenosine: MOA: slow conduction through the AV node. Interrupt re-entry through the AV node. 24
Mr. Gaurang Ramani
ADR: facial flushing, shortness of breath, chest
3.2 pressure, Nausea, headache. ANTIARRHYTHMIC AGENT
ATROPIN: 1-2 mg MOA: Block vegal effect on SA node ADR: Restlessness, headache, dizziness, blurred vision.
25
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
26
Mr. Gaurang Ramani
Definition: Cardiac arrhythmia are deviations from the normal heartbeat pattern. They include abnormalities of impulse formation, such as heart rate , rhythm, or site of impulse origin, and conduction disturbances, which disrupt the normal sequence of atrial and ventricular activation. Four main structures composed of tissue that can generate or conduct electrical impulses comprise the conduction system of the heart. The SA node, in the wall of the right atrium, contains cells that spontaneously initiate an action potential. Serving as the main pacemaker of the heart, the SA node initiates 60-100 beats/mins. Impulse generated by the SA node trigger atrial contraction. 2
Mr. Gaurang Ramani 3.2 ANTIARRHYTHMIC AGENT
3
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Impulses travel through intermodal tracts- the anterior tract, middle tract, posterior tract and anterior internal tract. At the AV node, situated in the lower interatrial septum, the impulses are delayed briefly to permit completion of atrial contraction before ventricular contraction begins. At the bundle of His-muscle fibers arising from the AV junctionimpulses travel along the left and right bundle branches, located on either side of the intraventricular septum. The impulses reach the Purkinje fibers, a diffuse network extending from the bundle branches and ending in the ventricular endocardial surfaces. Ventricular contraction then occurs. 4
Mr. Gaurang Ramani 3.2 ANTIARRHYTHMIC AGENT
Depolarization and repolarization result from changes in the electrical potential across the cell membrane, caused by the exchange of sodium and potassium ions. Action potential, which reflects this electrical activity, has five phases. Phase 0 (rapid depolarization) takes place as sodium ions enter the cell through fast channel; the cell membrane’s electrical charge changes from negative to positive. Phase 1 (early rapid repolarization). As fast sodium channel close and potassium ions leave the cell, the cell rapidly repolarizes (e.g. return to resting potential). Phase 2 (plateau). Calcium ions enter the cell through slow channels while potassium ions exit. As the cell membrane’s electrical activity temporarily stabilizes, the action potential reaches a plateau. 5
Mr. Gaurang Ramani 3.2 ANTIARRHYTHMIC AGENT
Phase 3 (final rapid polarization). Potassium ions are pumped out of the cell as the cell rapidly completes repolatization and resumes its initial negativity. Phase 4 (slow depolrization). The ell returns to its resting state with potassium ions inside the cell and sodium and calcium ions outside.
6
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
7
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Antiarrhythmic agents are a group of pharmaceuticals that are used to suppress fast rhythms of the heart (cardiac arrhythmias), such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation. Class I agents interfere with the sodium (Na+) channel. Class II agents are anti-sympathetic nervous system agents. Most agents in this class are beta blockers. Class III agents affect potassium (K+) efflux. Class IV agents affect calcium channels and the AV node. Class V agents work by other or unknown mechanisms.
8
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Class Ia
Ib
Ic
9
Mr. Gaurang Ramani
Examples •
Quinidine
•
Procainamide
•
Disopyramide
•
Lidocaine
•
Phenytoin
•
Mexiletine
•
Flecainide
•
Propafenone
•
Moricizine
3.2 ANTIARRHYTHMIC AGENT
II
III
IV
V
10
Mr. Gaurang Ramani
•
Propranolol
•
Esmolol
•
Timolol
•
Metoprolol
•
Atenolol
•
Amiodarone
•
Sotalol
•
Ibutilide
•
Dofetilide
•
Verapamil
•
Diltiazem
•
Adenosine
•
Digoxin 3.2 ANTIARRHYTHMIC AGENT
Class I agents The class I antiarrhythmic agents interfere with the sodium channel. Class I agents are grouped by what effect they have on the Na+ channel, and what effect they have on cardiac action potentials. Class 1 agents are called Membrane Stabilizing agents. Class I agents are divided into three groups (1a, 1b and 1c) based upon their effect on the length of the action potential. 1a lengthens the action potential (right shift) 1b shortens the action potential (left shift) 1c does not significantly affect the action potential (no shift) 11
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
12
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
MOA: It reduces the slope of phase 4 depolarization in pacemaker cells. This is probably due to a reduction of diastolic sodium influx. Thus it abolishes ectopic pacemakers activity. It also reduces the transfer of sodium across the cell membrane during phase 0 of the action potential. As a result the conduction velocity is decreased and the refractory period is prolonged. Due to the decreased sodium influx there is decreased efflux of potassium, which has a specific membrane stabilizing effect on the cardiac cell. The reduction in potassium efflux may be responsible for the increase in the duration of the action potential observed with Ia. It blocks open sodium (Na+) channels and prolongs the cardiac action potential. This results in slowed conduction, and ultimately the decreased rate of rise of the action potential.
13 Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Quinidine: 200-300 mg Side effects Thrombocytopenia (low platelet count) Cinchonism (headache, dizziness, hearing loss)with tinnitus (ringing in the ears), nausea, vomiting, diarrhea, confusion.
14
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Procainamide : 500-1000mg Side effects Rash,
Myalgia
(pain
in
muscle)
hypersensitivity
reactions
(fever,
agranulocytosis), Drug-Induced Lupus Erythematosus, and proarrhythmic. Treatment with procainamide can cause antibody production against cellular components, accounting for the systemic lupus erythematosus-like adverse reactions.
15
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Disopyramide: 400-800mg/day Cardiac Adverse Effects Acute heart failure Severe hypotension Extracardiac Effects Dry mouth Constipation Urinary retention Blurred vision Glaucoma Rash Agranulocytosis
16
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Class 1b
Class Ib agents shorten the action potential duration. These agents will decrease Vmax
in partially depolarized cells with fast response action
potentials. They either do not change the action potential duration, or they may decrease the action potential duration. Class Ib drugs tend to be much more specific for voltage gated Na channels than Ia. 17
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Lidocaine : 1-1.5 mg/kg Adverse drug reactions Allergic, tinnitus, tremor, dizziness, blurred vision, seizures, drowsiness, loss of consciousness, respiratory depression and apnea (sleep). Cardiovascular effects include hypotension, cardiac arrest Phenytoin: 300-400mg/day Side-effects Heart block, drowsiness, vertigo, nausea, megaloblastic anemia, leuckopenia, thrombocytopenia. Ataxia (Inability to coordinate voluntary muscle movements), Nystagmus (Involuntary movements of the eyeballs).
Mexiletine: 200-400 mg ADR: Dizziness, Ataxia, Nystagmus, Hypotension, Nausea, Vomiting.
18
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Class 1C
MOA: Class Ic antiarrhythmic agents markedly depress the phase 0 depolarization (decreasing Vmax ). It works by blocking the sodium channel in the heart, causing prolongation of the cardiac action potential. This thereby slows conduction of the electrical impulse within the heart. The greatest effect is on the His-Purkinje system and ventricular myocardium. Of the sodium channel blocking antiarrhythmic agents, the class Ic agents have the most potent sodium channel blocking effects. Class Ic agents are indicated for life-threatening ventricular tachycardia or ventricular fibrillation, and for the treatment of refractory supraventricular tachycardia (ie: atrial fibrillation). 19
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Flecainide: 50-100 mg/12 hrs Serious adverse reactions Dizziness, headache, treamor, nausea, abdominal pain Propafenone: 150 mg/8 hrs Side effects hypersensitivity reactions, lupus-like syndrome, agranulocytopenia, dizziness, lightheadedness (a feeling that you are about to fall), gastrointestinal upset, a metallic taste and bronchospasm.
20
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Class II agents MOA: Parasympathetic (vagal) activation decreases conduction velocity at the AV node by decreasing the slope of phase 0 of the nodal action potentials. This leads to slower depolarization of adjacent cells, and reduced velocity of conduction Class II agents are conventional beta blockers. They act by blocking the effects of catecholamines at the β1-adrenergic receptors, thereby decreasing sympathetic activity on the heart. These agents are particularly useful in the treatment of supraventricular tachycardias. They decrease conduction through the AV node. Propranolol: 10-80 mg/day ADR: fatigue, lethargy, increased airway resistance, skin rashes, nausea, vomiting, diarrhea. 21
Mr. Gaurang Ramani
ESOMOLOL: 50microg/kg/min
3.2 ANTIARRHYTHMIC AGENT
Class III agents MOA: Class III agents predominantly block the potassium channels, thereby prolonging repolarization. Since these agents do not affect the sodium channel, conduction velocity is not decreased. The prolongation of the action potential duration and refractory period, combined with the maintenance of normal conduction velocity, prevent re-entrant arrhythmias. AMIODARONE: 200-600 mg/day ADR:
Fatigue, malaise (mild sickness or depression), peripheral neuropathy,
extrapyramidal effect, nausea, vomiting SOTALOL: 160-480 mg/kg ADR: Bradycardia, myocardial depression, bronchospasm BRETYLIUM: 5mg/kg ADR: Nausea, vomiting 22
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Class IV agents MOA: Phase 0 of action potentials at the AV node is not dependent on fast sodium channels, but instead is generated by the entry of calcium into the cell through slow-inward calcium channels. Blocking these channels with a calcium-channel blocker such as verapamil or diltiazem reduces the conduction velocity of impulses through the AV node and can produce AV block. Class IV agents are slow calcium channel blockers. They decrease conduction through the AV node (Depression). Shorten phase two (the plateau) of the cardiac action potential. Verapamil 5-10 mg & Diltiazem 20 mg ADR: constipation and nausea 23
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
Other agents ("Class V") Since the development of the original Vaughan-Williams classification system, additional agents have been used that don't fit cleanly into categories I to IV. Some sources use the term "Class V" However, they are more frequently identified by their precise mechanism. Agents include: Digoxin, which decreases conduction of electrical impulses through the AV node and increases vagal activity via its central action on the central nervous system. Adenosine: MOA: slow conduction through the AV node. Interrupt re-entry through the AV node. 24
Mr. Gaurang Ramani
ADR: facial flushing, shortness of breath, chest
3.2 pressure, Nausea, headache. ANTIARRHYTHMIC AGENT
ATROPIN: 1-2 mg MOA: Block vegal effect on SA node ADR: Restlessness, headache, dizziness, blurred vision.
25
Mr. Gaurang Ramani
3.2 ANTIARRHYTHMIC AGENT
26
Mr. Gaurang Ramani
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