Autonomic Nervous System & Anti-Dysrhythmic Drugs

Autonomic Nervous System Effects on Heart and Other Organs

• The sympathetic nervous system has a preganglionic neuron that releases ACH, which acts on nicotinic ACH receptors.
• The postganglionic neuron releases noradrenaline (NA), which acts on different adrenergic receptors (AR) at end organs.

Adrenergic Receptors

• α1 receptors: smooth muscle contraction, vasoconstriction in viscera, and GI motility.
• β1 receptors: heart frequency, contractile force, and conduction at A-V node.
• β2 receptors: smooth muscle relaxation, vasodilation in skeletal muscle, and bronchi dilation.

Sympathetic Nervous System: Adrenergic Receptors

• Preganglionic neurons release ACH, which acts on nicotinic ACH receptors.
• Postganglionic neurons release NA, which acts on different AR at end organs.
• Effects of sympathetic nervous system on different organs:
  • Eyes: pupillary dilation.
  • Heart: increased heart rate.
  • Lungs: bronchi dilation.
  • Liver: increased glycogenolysis.
  • Stomach and intestines: increased motility and secretions.
  • Arteries and veins: increased blood pressure and redistribution of blood flow away from GI tract.

Muscarinic Acetylcholine Receptors

• ACH release and breakdown by ACH esterase.
• Muscarinic receptors:
  • M1: IP3/DAG signaling in CNS, glands, and smooth muscle.
  • M2: cAMP signaling in heart and CNS.
  • M3: IP3/DAG signaling in smooth muscle and glands.
  • M4: cAMP signaling in smooth muscle and glands.
  • M5: IP3/DAG signaling in smooth muscle and glands.
• Effects of muscarinic receptors:
  • SLUDGE (Salivation, Lacrimation, Urination, Defecation, Gastrointestinal motility, and Emesis) or DUMBELS (Diarrhea, Urination, Miosis, Bronchorrhea, Bronchospasm, and Emesis).

Anti-Dysrhythmic Drugs

• Classification of anti-dysrhythmic drugs according to the Vaughan Williams system:
  • Class I: sodium channel blockers.
  • Class II: β-adrenoreceptor antagonists.
  • Class III: drugs that prolong the cardiac action potential.
  • Class IV: calcium channel antagonists.

Class I – Na+ Channel Blockers

• Mechanism of action: block voltage-sensitive sodium channels.
• Effects: slow conduction velocity of pacemaker potentials throughout the heart and affect myocyte action potentials.
• Used for: ventricular and atrial tachyarrhythmias.
• Side effects: bradycardia and potential worsening of arrhythmias.
• Subclasses:
  • Ia: dissociation within < 0.5 sec.
  • Ib: highly frequency-dependent, used for bradyarrhythmia (i.v.).

Digitalis

• Used for heart failure and some arrhythmias to increase ventricular output.
• Mechanism of action:
  • Inhibition of NaK-ATPase, leading to increased [Na+]i and [Ca++]i.
  • Increased vagal tone, leading to cardiac slowing and reduced rate of conduction through AV node.
  • Increased [Ca++]i, leading to increased twitch tension and increased chance of afterdepolarisations and tachycardia.

Muscarinic Antagonist Effects

• Dry mouth and eyes.
• Urinary retention.
• Slowing of digestion.
• Constipation.
• Tachycardia.
• Bronchodilation.
• Less mucus production.
• Less sweating.
• Mydriasis.
• Loss of accommodation, leading to blurred vision.

Study Questions

• Which anti-dysrhythmic drugs have negative chronotropic side effects?
• Which drugs and drug classes act on:
  • Voltage-gated sodium channels.
  • Potassium channels.
  • Voltage-gated sodium channels.
  • Voltage-gated calcium channels.
• How do you treat bradycardia?
• What is the mechanism of action of these drugs?
• How do sodium channel blockers target only the most active channels?