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Cardiac arrhythmia drugs

This document discusses various drugs used to treat cardiac arrhythmias. It begins by describing the normal physiological conduction of the heart and different types of arrhythmias. It then classifies arrhythmia drugs into 5 groups based on their mechanisms of action and effects on ion channels. The majority of the document focuses on Group 1 drugs which block sodium channels. It provides details on the mechanisms, pharmacokinetics, dosages and adverse effects of specific Group 1 drugs including procainamide, quinidine, disopyramide, lidocaine, mexiletine, flecainide and propafenone.

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CARDIAC ARRHYTHMIA DRUGS Presented to: Dr. F. Deane Presenter : Shenellie Harry Course: Pharmacology Class: Med 4
NORMAL PHYSIOLOGICAL CONDUCTION OF THE HEART
NORMAL PHYSIOLOGICAL CONDUCTION OF THE HEART SA node activity and atrial activation begins Stimulus spreads across the atrial surfaces and reaches the AV node There is a 100-msec delay at the AV node, atrial contraction begins the impulse travels along the interventricular septum within the AV bundle and the bundle branches To the purkinjie fibers and via the moderator band to the papillary muscles of the right ventricle The impulse is distributed and relayed throughout the ventricular myocardium .
CARDIAC ARRHYTHMIA An arrhythmia is a problem with the rate or rhythm of the heartbeat. Tachycardia arrhythmia, where the heart can beat too Bradycardia ā€¢ Arrhythmia where the heart beats too slow ā€¢ or with an irregular rhythm
EXAMPLES OF ARRHYTHMIAS Atrial flutter Atrial fibrillation Ventricular tachycardia premature ventricular beats atrioventricular nodal reentry Ventricular fibrillation Torsades de pointes
MECHANISMS FOR ARRHYTHMIAS MECHANISM ABNORMAL AUTOMATICITY Pacemaker activity that originates anywhere other than in the sinoatrial node ABNORMAL CONDUCTION Conduction of an impulse that does not follow the pathway Re- enters tissue previously excited
CLASSIFICATION OF ARRHYTHMIA DRUGS Arrhythmia Drugs Group 1- sodium channel blockers Group 3- potassium channel blockers Group 4- Calcium channel blockers Group 2- beta blockers Group 5- Miscellaneous
GROUP 1- SODIUM BLOCKERS ā€¢ These drugs are classified based on their effects on the action potential duration. Group 1A Group 1B Group 1C
GROUP 1A These drugs affect both atrial andventricular arrhythmias. They block INa and therefore slow conduction ventricular arrhythmias. They block INa and therefore slow conduction
PROCAINAMIDE: MECHANISM OF ACTION During an action potential, voltage-gated sodium channels open, allowing sodium ions to diffuse across the membrane down their electrochemical gradient, further depolarizing the membrane of the cell. Blocking these channels slows conductivity and thereby prolongs the action potential and the refractory period. This results in an increase in the refractory period and a decrease in excitability and impulse conduction velocity of the atria and ventricles, relieving symptoms of arrhythmia and tachycardia. Procainamide also has weak vagolytic activity, which can result in an increased heart rate and other side effects. Procainamide can be metabolized in the liver to N- acetylprocainamide, a metabolite that also has antiarrhythmic action and slower renal clearance than procainamide, effectively increasing the therapeutic half-life of the drug.
PHARMACOKINETICS AND DOSAGE Procainamide can be administered safely by intravenous and intramuscular routes and is well absorbed orally. Excessive accumulation of NAPA has been implicated in torsades de pointes during procainamide therapy, especially in patients with renal failure. Procainamide is eliminated by hepatic metabolism to NAPAand by renal elimination. Its half-life is only 3ā€“4 hours, which necessitates frequent dosing or use of a slow-release formulation
PHARMACOKINETICS AND DOSAGE NAPA is eliminated by the kidneys. Thus,procainamide dosage must be reduced in patients with renal failure. The reduced volume of distribution and renal clearance associated with heart failure also require reduction in dosage. The half-life of NAPA is considerably longer than that of procainamide , and it therefore accumulates more slowly.
PHARMACOKINETICS AND DOSAGE- PROCAINAMIDE If a rapid procainamide effect is needed, an intravenous loading dose of up to 12 mg/kg can be given at a rate of 0.3 mg/kg/min or less rapidly. This dose is followed by a maintenance dosage of 2ā€“5 mg/min, with careful monitoring of plasma levels. The risk of gastrointestinal (GI) or cardiac toxicity rises at plasma concentrations greater than 8 mcg/mL or NAPA concentrations greater than 20 mcg/mL
PHARMACOKINETICS AND DOSAGE To control ventricular arrhythmias, a total procainamide dosage of 2ā€“5 g/d is usually required. In an occasional patient who accumulates high levels of NAPA, less frequent dosing may be possible. This is also possible in renal disease, where procainamide elimination is slowed.
ADVERSE EFFECTS OF PROCAINAMIDE Adverse effects Pericarditis arthralgia and arthritis parenchymal pulmonary disease nausea and diarrhea rash, fever, hepatitis
QUINIDINE : MECHANISM OF ACTION Quinidine stabilizes the neuronal membrane by binding to and inhibiting voltage-gated sodium channels, thereby inhibiting the sodium influx required for the initiation and conduction of impulses. This results in an increase of the threshold for excitation and decreased depolarization during phase 0 of the action potential. The drug also prolongs the action potential duration by blockadeof several potassium channels
QUINIDINE : PHARMACOKINETICS AND DOSAGE 100 to 600 mg/dose orally every 4 to 6 hours; begin at 200 mg/dose and titrate to desired effect (maximum daily dose: 3 to 4 g). The elimination of quinidine is accomplished by a combination of renal excretion of the intact drug (15 to 40% of total clearance) and hepatic biotransformation to a variety of metabolites (60 to 85% of total clearance). Quinidine is readily absorbed from the GI tract.
ADVERSE EFFECTS diarrhoea, nausea, and vomiting tinnitus (cinchonism) thrombocytopenia, hepatitis, angioneurotic edema, fever
DISOPYRAMIDE: MECHANISM OF ACTION Decreases the disparity in refractoriness between infarcted and adjacent normally perfused myocardium, and has no effect on alpha- or beta-adrenergic receptors. Decreases the upstroke velocity (phase 0) and increases the action potential duration of normal cardiac cells. Disopyramide decreases the rate of diastolic depolarization (phase 4) in cells with augmented automaticity. Inhibits the fast sodium channels.
DISOPYRAMIDE: PHARMACOKINETICS AND DOSAGE disopyramide is only available for oral use. The typical oral dosage of disopyramide is 150 mg three times a day, but up to 1 g/d has been used. In patients with renal impairment, dosage must be reduced.
DISOPYRAMIDE :ADVERSE EFFECTS worsening of pre-existing glaucoma constipation, blurred vision, Dry mouth, Urinary retention (most often, but not exclusively, in male patients with prostatic hyperplasia),
GROUP 1B: These are the most selective agents which have significant effects on sodium channels in ischemic tissue. However, they have negligible effects on channels in normal cells.
LIDOCAINE: MECHANISM OF ACTION The increased inactivation and slower unbinding kinetics result in the selective depression of conduction in depolarized cells The rapid kinetics at normal resting potentials result in recovery from block between action potentials and no effect on conduction. the inactivated state block ensures greater effects on cells with long action potentials such as Purkinje and ventricular cells, compared with atrial cells. Lidocaine blocks activated and inactivated sodium channels with rapid kinetics ;
LIDOCAINE : PHARMACOKINETICS AND DOSAGE In adults, a loading dose of 150ā€“200 mg administeredover about 15 minutes (as a single infusion or as a series of slow boluses) should be followed by a maintenance infusion of 2ā€“4mg/min to achieve a therapeutic plasma level of 2ā€“6 mcg/mL. Lidocaine has a half-life of 1ā€“2 hours. Thus, lidocaine must be given parenterally. Lidocaine goes through first-pass hepatic metabolism, only 3% of orally administered Lidocaine appears in the plasma.
LIDOCAINE: ADVERSE EFFECTS paresthesias, tremor, nausea of central origin, lightheadedness, hearing disturbances, slurred speech, convulsions
MEXILETINE: MECHANISM OF ACTION Mexiletine, like lidocaine, inhibits the inward sodium current, thus reducing the rate of rise of the action potential, Phase 0. Mexiletine decreased the effective refractory period (ERP) in Purkinje fibers.
MEXILETINE: PHARMACOKINETICS AND DOSAGE Mexiletine is well absorbed (~90%) from the gastrointestinal tract. Its first-pass metabolism is low. Peak blood levels are reached in two to three hours. The elimination half-life is 8ā€“20 hours and permits administration two or three times per day. The usual daily dosage of mexiletine is 600ā€“1200 mg/d.
MEXILETINE: ADVERSE EFFECTS Tremor Blurred vision Lethargy Nausea
GROUP 1C Group 1C drugs have no effect on AP duration. In contrast to group 1B it can cause some reduction of INa even in normal cells.
FLECAINIDE: MECHANISM OF ACTION Flecainide is a potent blocker of sodium and potassium channels with slow unblocking kinetics. Although it does block certain potassium channels, it does not prolong the action potential or the QT interval. Flecainide is very effective in suppressing premature ventricular contractions. However, it may cause severe exacerbation of arrhythmia even when normal doses are administered to patients with preexisting ventricular tachyarrhythmias and those with a previous myocardial infarction and ventricular ectopy.
FLECAINIDE: PHARMACOKINETICS AND DOSAGE Flecainide is well absorbed and has a half-life of approximately 20 hours. Elimination is both by hepatic metabolism and by the kidney. The usual dosage of flecainide is 100ā€“ 200 mg twice a day.
PROPAFENONE: MECHANISM OF ACTION The electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and to a lesser extent myocardial fibers, propafenone reduces the fast inward current carried by sodium ions, which is responsible for the drugs antiarrhythmic actions. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity.
PROPAFENONE : PHARMACOKINETICS AND DOSAGE Propafenone is metabolized in the liver, with an average half-life of 5ā€“7 hours. The usual daily dosage of propafenone is 450ā€“ 900 mg in three divided doses.
MORICIZINE: MECHANISM OF ACTION Moricizine works by inhibiting the rapid inward sodium current across myocardial cell membranes. Moricizine has potent local anesthetic activity and membrane stabilizing effect. Decreases excitability, conduction velocity, and automaticity as a result of slowed atrioventricular (AV) nodal and His-Purkinje conduction. Decreases the action potential duration (APD) in Purkinje fibers; also decreases the effective refractory period (ERP).
MORICIZINE : PHARMACOKINETICS AND DOSAGE well absorbed, absorption is complete within 2 to 3 hours. Metabolized in the liver.
(CLASS 2 )PROPRANOLOL : MECHANISM OF ACTION Propranolol competes with sympathomimetic neurotransmitters such as catecholamines for binding at beta(1)-adrenergic receptors in the heart, inhibiting sympathetic stimulation. This results in a reduction in resting heart rate, cardiac output, systolic and diastolic blood pressure, and reflex orthostatic hypotension
PROPRANOLOL: PHARMACOKINETICS AND DOSAGE Propranolol is highly lipophilic and almost completely absorbed after oral administration. However, it undergoes high first-pass metabolism by the liver and on average, only about 25% of propranolol reaches the systemic circulation. Peak plasma concentrations occur about 1 to 4 hours after an oral dose. 10 to 30 mg orally 3 to 4 times a day, before meals and at bedtime.
PROPRANOLOL: ADVERSE EFFECTS nausea, vomiting, diarrhea, constipation, stomach cramps, rash, deceased sex drive, impotence, or difficulty having an orgasm.
ESMOLOL: MECHANISM OF ACTION
Cardiac arrhythmia drugs