Comprehensive Overview of Antiarrhythmic Drugs

Antiarrhythmic Drugs

Classification & Mechanism of Action
Indications, Adverse Effects, Contraindications, and Drug Interactions
Focus on Quinidine, Amiodarone, Adenosine, and Isoprenaline

Classification of Antiarrhythmic Drugs (Vaughan-Williams Classification)

Class I: Sodium Channel Blockers (Membrane stabilizing drugs)

IA: Quinidine (Moderate Na⁺ blockade, prolongs APD)

IB: Lidocaine, Mexiletine (Weak Na⁺ blockade, shortens APD)

IC: Flecainide, Propafenone (Strong Na⁺ blockade, no effect on APD)

Class II: Beta-Blockers (e.g., Propranolol, Esmolol)

Class III: Drugs widening AP: Potassium Channel Blockers (e.g., Amiodarone)

Class IV: Calcium Channel Blockers (e.g., Verapamil, Diltiazem)

Miscellaneous:

Paroxysmal supraventricular tachycardia (PSVT): (e.g., Adenosine),

Atrio-ventricular Block (A-V Block)(e.g., Isoprenaline)

Membrane Stabilizing Drug – Quinidine

Mechanism of Action:

Blocks Na⁺ channels, slowing phase 0 depolarization
Blocks K⁺ channels, prolonging APD & refractory period
Inhibits vagal effects, increasing conduction through AV node

Indications:

Atrial fibrillation & flutter
Ventricular tachycardia
Wolff-Parkinson-White (WPW) syndrome

Adverse Effects:

Torsades de Pointes (QT prolongation)
Hypotension, dizziness
Cinchonism (headache, tinnitus, blurred vision)

Contraindications:

Long QT syndrome
Heart block
Myasthenia gravis

Drug Interactions:

Increases digoxin toxicity
Enhanced effects with CYP3A4 inhibitors

Drug Widening AP – Amiodarone

Mechanism of Action:

Blocks K⁺ channels, prolonging APD & refractory period
Also blocks Na⁺, Ca²⁺ channels & β-receptors

Indications:

Atrial fibrillation & ventricular arrhythmias
WPW syndrome

Adverse Effects:

Pulmonary fibrosis
Thyroid dysfunction (hypo/hyperthyroidism)
Corneal deposits & skin discoloration

Contraindications:

Severe lung disease
Iodine allergy

Drug Interactions:

Increases levels of warfarin, digoxin, statins

Paroxysmal Supraventricular Tachycardia (PSVT) – Adenosine

Mechanism of Action:

Activates A1 receptors in AV node → Inhibits Ca²⁺ influx, increases K⁺ efflux
Hyperpolarization → Transient AV block

Indications:

First-line drug for PSVT

Adverse Effects:

Flushing, chest pain, dyspnea
Transient asystole

Contraindications:

Asthma (bronchospasm risk)
Severe hypotension, heart block

Drug Interactions:

Theophylline & caffeine reduce effect

Atrio-Ventricular (AV) Block – Isoprenaline

Mechanism of Action:

β1 & β2 agonist → Increases HR & AV conduction

Indications:

AV block, bradycardia, cardiac arrest

Adverse Effects:

Tachycardia, arrhythmias, hypotension

Contraindications:

Acute MI, tachyarrhythmias

Drug Interactions:

Increased risk with other sympathomimetics

Pharmacokinetics of Quinidine (Detailed Explanation)

Absorption (How Quinidine Enters the Bloodstream)

Route of Administration:

Primarily oral (tablet or extended-release)
Can be given IV, but rarely used due to toxicity risk.

Bioavailability:

70–80% (well absorbed from the gastrointestinal tract)
Some portion is metabolized by the liver before entering systemic circulation (first-pass metabolism).

Factors Affecting Absorption:

✔ Food: Delays absorption but does not affect total amount absorbed.
✔ Gastric pH: Higher stomach acidity can increase absorption.
✔ Drug Interactions:

Antacids, proton pump inhibitors (PPIs) → May reduce absorption.
CYP3A4 inhibitors (e.g., ketoconazole) → Increase quinidine levels.

Distribution (How Quinidine Spreads in the Body)

Plasma Protein Binding:

80–90% bound to albumin, meaning only 10–20% of the drug is active at a given time.
Low protein levels (hypoalbuminemia) increase free quinidine levels, raising toxicity risk.

Volume of Distribution (Vd):

2–3 L/kg (moderate distribution in tissues).
Lipophilic (fat-soluble), allowing it to enter cardiac and nervous tissue.
Crosses the blood-brain barrier (BBB) → can cause CNS side effects (e.g., confusion, dizziness).
Crosses the placenta and can be present in breast milk (use caution in pregnancy & breastfeeding).

Tissue Distribution:

Highest in the heart, liver, and kidneys.
Accumulates in skeletal muscle → may contribute to muscle-related side effects.

Clinical Note: Quinidine’s CNS penetration contributes to cinchonism (headache, tinnitus, dizziness, vision changes).

Metabolism (How Quinidine is Broken Down)

Site of Metabolism:

Primary metabolism occurs in the liver.
CYP3A4 enzyme converts quinidine into 3-hydroxyquinidine (active metabolite, but less potent).

Metabolism Pathways:

✔ Phase I: Oxidation by CYP3A4 (major pathway).
✔ Phase II: Glucuronidation (makes it water-soluble for excretion).

Factors Affecting Metabolism:

✔ Liver Disease → Slows metabolism, increasing drug levels & toxicity risk.
✔ CYP3A4 Inhibitors (increase quinidine levels):

Ketoconazole, erythromycin, grapefruit juice
✔ CYP3A4 Inducers (decrease quinidine levels):
Rifampin, phenytoin, phenobarbital

Excretion (How Quinidine Leaves the Body)

Primary Routes of Excretion:

✔ Kidneys (~20% excreted unchanged in urine).
✔ Liver/Biliary System (~80% metabolized and excreted in bile & feces).

Renal Clearance:

Urinary pH affects excretion:

Acidic urine → Increases quinidine elimination.
Alkaline urine → Reduces elimination, increasing toxicity risk.

Half-Life (t½):

6–8 hours (varies with liver/kidney function).
Extended in patients with renal or hepatic dysfunction, requiring dose adjustments.

Pharmacokinetics of Amiodarone

Absorption (How Amiodarone Enters the Bloodstream)

Route of Administration:

✔ Oral (Tablets) → Most common for chronic treatment.
✔ Intravenous (IV) → Used for acute life-threatening arrhythmias.

Bioavailability:

Poor oral bioavailability (30-50%) due to extensive first-pass metabolism in the liver.
Food increases absorption, so it should be taken with meals.

Factors Affecting Absorption:

✔ First-pass metabolism in the liver reduces the amount reaching circulation.
✔ Highly variable among patients due to differences in liver metabolism.
✔ Drug interactions:

CYP3A4 inhibitors (e.g., grapefruit juice, ketoconazole) → Increase amiodarone levels.
CYP3A4 inducers (e.g., rifampin) → Decrease amiodarone levels.

Clinical Note: Since bioavailability varies among patients, dosing adjustments are often needed.

Distribution (How Amiodarone Spreads in the Body)

Plasma Protein Binding:

Highly protein-bound (~96%), meaning a large portion of the drug is inactive at any given time.

Volume of Distribution (Vd):

Extremely high (60 L/kg), indicating extensive distribution in tissues.
Highly lipophilic (fat-soluble), meaning it accumulates in:
✔ Fat tissue
✔ Liver
✔ Lungs
✔ Heart and muscles

Tissue Accumulation:

Due to its lipophilicity, amiodarone takes weeks to months to reach steady-state levels in the body.
Crosses the placenta and is found in breast milk → Not recommended in pregnancy & breastfeeding.

Clinical Note: Due to tissue accumulation, effects persist for weeks to months after stopping the drug.

Metabolism (How Amiodarone is Broken Down)

Site of Metabolism:

✔ Primarily metabolized in the liver by the CYP3A4 enzyme.
✔ Converts to desethylamiodarone (DEA), an active metabolite that contributes to its effects.

Metabolism Pathways:

✔ Phase I: Oxidation by CYP3A4 (major) & CYP2C8 (minor).
✔ Phase II: Conjugation for excretion.

Factors Affecting Metabolism:

✔ Liver dysfunction → Reduces metabolism, leading to drug accumulation.
✔ CYP3A4 inhibitors (increase amiodarone levels):

Ketoconazole, erythromycin, grapefruit juice.
✔ CYP3A4 inducers (decrease amiodarone levels):
Rifampin, phenytoin, St. John’s Wort.

Excretion (How Amiodarone Leaves the Body)

Primary Routes of Excretion:

✔ Hepatic (Biliary/Fecal) → Major route (~95%).
✔ Renal (Urine) → Minimal (~5%).

Half-Life (t½):

Extremely long (20-100 days), average ~58 days.
Active metabolite (DEA) also has a long half-life (~40 days).

Pharmacokinetics of Adenosine

Absorption (How Adenosine Enters the Bloodstream)

Route of Administration:

✔ Intravenous (IV) bolus → The only route used clinically.
✔ Not given orally because it would be rapidly degraded in the gastrointestinal tract.

Bioavailability:

Not applicable, as adenosine is only given IV and does not undergo absorption from the GI tract.

Distribution (How Adenosine Spreads in the Body)

Plasma Protein Binding:

Negligible (almost none).
Since adenosine is a naturally occurring purine nucleoside, it is freely distributed in plasma.

Volume of Distribution (Vd):

Very low (~0.15 L/kg), meaning adenosine remains mostly in the plasma and extracellular fluid.
Does not accumulate in tissues due to rapid uptake and metabolism.

Metabolism (How Adenosine is Broken Down)

Site of Metabolism:

✔ Primarily metabolized in blood and tissues by erythrocytes (RBCs) and vascular endothelial cells.

Metabolism Pathways:

✔ Rapid deamination by the enzyme adenosine deaminase (ADA) into inosine, which is inactive.
✔ Further breakdown into hypoxanthine, xanthine, and uric acid for excretion.

Factors Affecting Metabolism:

✔ Genetic variations in ADA activity (rare) may slightly alter adenosine metabolism.
✔ Methylxanthines (e.g., caffeine, theophylline) → Inhibit adenosine receptors, reducing effectiveness.
✔ Dipyridamole (antiplatelet drug) → Inhibits adenosine uptake, increasing its effects.

Excretion (How Adenosine Leaves the Body)

Primary Routes of Excretion:

✔ Metabolites (inosine, hypoxanthine, xanthine, uric acid) are excreted by the kidneys.
✔ Adenosine itself is not excreted directly in urine because it is almost completely metabolized before reaching the kidneys.

Half-Life (t½):

Less than 10 seconds (average = 0.6–1.5 seconds).
Because of this ultra-short half-life, adenosine must be administered as a rapid IV bolus to be effective.

Pharmacokinetics of Isoprenaline

1. Absorption

Route of administration: Isoprenaline is usually administered intravenously, but it can also be administered by inhalation (aerosol), or subcutaneously.
Bioavailability: When administered orally, isoprenaline has poor bioavailability due to significant first-pass metabolism in the liver, so it's rarely given by this route. When given intravenously or via inhalation, its bioavailability is almost 100% because it bypasses the liver's first-pass effect.

2. Distribution

Volume of Distribution (Vd): Isoprenaline has a moderate volume of distribution, typically around 2–5 L/kg. The drug is distributed throughout the body, particularly to the heart, lungs, liver, and kidneys.
Plasma Protein Binding: Isoprenaline binds weakly to plasma proteins (approximately 10-30%).
Crosses the Blood-Brain Barrier (BBB): Isoprenaline crosses the blood-brain barrier to a limited extent. This is relevant when considering its central nervous system (CNS) side effects (e.g., anxiety, restlessness).

3. Metabolism

Primary route of metabolism: Isoprenaline is metabolized primarily in the liver by enzymes such as catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO).
Metabolites: The main metabolites of isoprenaline are inactive compounds. The major metabolites include:

3-O-methylisoprenaline (via COMT).
Normetabolites from the action of MAO.

First-pass effect: Isoprenaline undergoes substantial first-pass metabolism when taken orally, which significantly reduces its systemic availability.

4. Excretion

Half-life: The plasma half-life of isoprenaline is relatively short, usually around 2–5 minutes when administered intravenously. This short half-life is due to rapid metabolism and excretion.
Elimination Route: Isoprenaline is primarily excreted via the kidneys in the form of its inactive metabolites.

Urinary Excretion: A small fraction of the unchanged drug is excreted in urine, but most is excreted as metabolites.

5. Pharmacodynamic Effects

Mechanism of action: Isoprenaline acts as a non-selective beta-adrenergic agonist, primarily stimulating beta-1 and beta-2 receptors.

Beta-1 receptor stimulation results in an increase in heart rate (positive chronotropic effect), contractility (positive inotropic effect), and conduction velocity in the heart.
Beta-2 receptor stimulation leads to smooth muscle relaxation, particularly in the bronchi, which is why it is also used in managing conditions like asthma.

Onset of Action: When given intravenously, the onset of action is almost immediate (within minutes).
Duration of Action: The duration of action is relatively short-lived, lasting 1-2 hours after an intravenous dose.

6. Therapeutic Uses

Cardiovascular: Used to treat bradycardia, heart block, and low cardiac output states. It increases heart rate and improves myocardial contractility.
Pulmonary: Inhaled isoprenaline is used for bronchospasm relief in conditions like asthma or chronic obstructive pulmonary disease (COPD).
Other uses: Occasionally used for other conditions that require increased heart rate or bronchodilation.

7. Side Effects

Due to its beta-adrenergic activity, isoprenaline can cause:

Cardiovascular: Tachycardia, palpitations, arrhythmias, increased myocardial oxygen demand (which may be problematic in certain patients with coronary artery disease).
Central Nervous System: Anxiety, restlessness, tremors, headache.
Respiratory: Can paradoxically lead to bronchospasm in some patients, especially if used excessively.
Metabolic: Hyperglycemia, hypokalemia (due to beta-2 stimulation).

8. Pharmacokinetic Variability

Age: In elderly patients, clearance may be reduced due to age-related changes in liver function, potentially leading to prolonged effects.
Renal Impairment: Since excretion is largely renal, impaired kidney function can result in accumulation of metabolites.
Hepatic Impairment: Patients with liver dysfunction may have reduced clearance of isoprenaline, leading to prolonged pharmacodynamic effects.

Presentation for Antiarrhythmic Drugs

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