Anticholinergic chronotropic agents

Introduction

Chronotropic agents influence the rate of the heart beat. Positive chronotropic drugs increase heart rate, while negative chronotropes decrease it. Anticholinergic chronotropic agents are a subset of antimuscarinic drugs that increase heart rate primarily by blocking parasympathetic (vagal) tone at muscarinic M2 receptors in the sinoatrial (SA) node.

They are used in conditions such as symptomatic bradycardia, atrioventricular (AV) block, and certain emergency situations requiring rapid reversal of vagally mediated bradyarrhythmias.

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Mechanism of Action

• Primary target: Muscarinic acetylcholine (M2) receptors in the heart.

• Action: Inhibits vagal influence on SA and AV nodes → increases firing rate of the SA node and conduction through the AV node.

• Effect: Positive chronotropy (↑ heart rate) and positive dromotropy (↑ AV conduction).

• Secondary effects: Reduction of secretions (salivary, respiratory), bronchodilation, pupillary dilation (mydriasis).

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Major Agents

1. Atropine

• Mechanism: Non-selective muscarinic antagonist; blocks M2 receptors in the heart.

• Uses:

  • First-line drug in symptomatic sinus bradycardia (advanced cardiac life support, ACLS).

  • Management of AV nodal block (not effective in complete heart block).

  • Antidote for organophosphate or carbamate poisoning (which cause excessive cholinergic activity and bradycardia).

• Administration: Intravenous (IV) bolus; repeated dosing possible.

• Adverse Effects: Dry mouth, blurred vision, urinary retention, constipation, delirium (especially in elderly), tachyarrhythmias.

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2. Hyoscyamine

• Mechanism: Muscarinic antagonist, similar to atropine but longer acting.

• Uses: Primarily GI spasm and irritable bowel syndrome, but also has chronotropic effect if given systemically.

• Adverse Effects: Same as atropine, more pronounced CNS effects due to good penetration.

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3. Glycopyrrolate

• Mechanism: Quaternary ammonium antimuscarinic (does not cross blood–brain barrier).

• Uses:

  • Reduces vagal reflex–induced bradycardia during surgery or anesthesia.

  • Preoperative reduction of secretions.

• Advantages: Less CNS toxicity compared to atropine.

• Adverse Effects: Tachycardia, dry mouth, constipation, urinary retention (but little CNS confusion).

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4. Ipratropium / Tiotropium (Inhaled antimuscarinics)

• Mechanism: Block M3 receptors in the airways, but also weakly block cardiac M2 receptors.

• Chronotropic Effect: Minimal when inhaled, but systemic absorption can cause modest tachycardia.

• Clinical Use: Not primarily used as chronotropic agents, but effect noted in patients with COPD/asthma.

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Clinical Indications

1. Emergency Bradycardia (ACLS protocol):

   • Atropine is the first-line treatment for unstable bradycardia (0.5 mg IV every 3–5 minutes up to 3 mg).

2. AV Nodal Block (Mobitz I / vagally mediated block):

   • Atropine improves AV conduction.

   • Ineffective in infranodal blocks (Mobitz II or complete heart block).

3. Organophosphate Poisoning:

   • Atropine reverses life-threatening bradycardia, bronchorrhea, and bronchospasm.

4. Anesthesia / Surgery:

   • Glycopyrrolate or atropine used to prevent vagally mediated bradycardia during intubation or surgical procedures.

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Contraindications

• Narrow-angle glaucoma.

• Tachyarrhythmias (e.g., atrial fibrillation with rapid ventricular response, untreated thyrotoxicosis).

• Severe obstructive uropathy (urinary retention).

• Myasthenia gravis (may worsen weakness).

• Elderly patients prone to confusion/delirium (avoid CNS-penetrating agents like atropine, hyoscyamine, scopolamine when possible).

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Adverse Effects (Anticholinergic Syndrome)

• Cardiac: Tachycardia, palpitations, possible arrhythmias.

• CNS: Confusion, agitation, hallucinations (especially with atropine, scopolamine).

• Ocular: Blurred vision, mydriasis, increased intraocular pressure.

• GI/GU: Dry mouth, constipation, urinary retention.

• Skin: Decreased sweating, hyperthermia (in high doses).

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Clinical Considerations

1. Atropine in ACLS: First-line drug for symptomatic bradycardia, but if ineffective, pacing or alternative agents (dopamine, epinephrine) are used.

2. Glycopyrrolate advantage: Useful when anticholinergic chronotropic effect is desired without CNS effects.

3. Caution in elderly: CNS toxicity from atropine and related drugs is common; glycopyrrolate is safer.

4. Combination therapy: Sometimes paired with acetylcholinesterase inhibitors (e.g., neostigmine reversal of neuromuscular blockade) to prevent reflex bradycardia.

5. Dose-dependent effects: Low-dose atropine can paradoxically cause transient bradycardia before tachycardia (due to presynaptic M1 blockade).