Autonomic Drugs in Respiratory Disease

Autonomic Innervation: Airways - The Breath Conductors

• Sympathetic (SNS): Bronchodilation
  • $\beta_2$ receptors (smooth muscle) $\rightarrow$ Relaxation (Bronchodilation).
  • Pathway: $\beta_2 \rightarrow G_s \rightarrow \uparrow \text{cAMP}$.
  • 📌 B for Beta, B for Bronchodilation.
• Parasympathetic (PNS): Bronchoconstriction & Secretion
  • $M_3$ receptors (smooth muscle) $\rightarrow$ Contraction (Bronchoconstriction).
  • $M_3$ receptors (glands) $\rightarrow \uparrow$ Mucus.
  • Pathway: $M_3 \rightarrow G_q \rightarrow \uparrow \text{IP}_3/\text{DAG} \rightarrow \uparrow \text{Ca}^{2+}$.
  • 📌 M for Muscarinic, M for Mucus & Muscle constriction.


⭐ Non-selective beta-blockers (e.g., propranolol) can precipitate bronchospasm in asthmatics by blocking $\beta_2$ receptors.

β2-Adrenergic Agonists - Bronchial Liberators

• Mechanism: Selective $\beta_2$ agonism $\rightarrow G_s \rightarrow \uparrow \text{adenylyl cyclase} \rightarrow \uparrow \text{cAMP} \rightarrow \text{PKA} \rightarrow$ smooth muscle relaxation.

• Classification:

  • SABA (Short-Acting): Rapid onset, duration 4-6h.
    • Examples: Salbutamol, Levosalbutamol, Terbutaline.
    • 📌 SABA: 'SAlbutamol Saves Acute Breathlessness'.
  • LABA (Long-Acting): Slow onset (except Formoterol: rapid), duration ~12h.
    • Examples: Salmeterol, Formoterol.
    • 📌 LABA: 'SALMON FORmula lasts longer' (SALMeterol, FORMOTerol).
  • Ultra-LABA: Duration ~24h.
    • Examples: Indacaterol.

• Comparison:

  Feature	SABA	LABA
  Key Role	Reliever	Controller

• Uses: Asthma (SABA for rescue; LABA+ICS for control), COPD, Exercise-Induced Bronchospasm (EIB).

• Adverse Effects: Tremor, tachycardia, palpitations, hypokalemia (📌 K+ influx into cells!), hyperglycemia, tachyphylaxis.

• Route: Inhalation preferred.

⭐ Formoterol is a LABA with a rapid onset of action, comparable to SABAs, making it suitable for both reliever and maintenance therapy (in combination with ICS).

Muscarinic Antagonists - Vagal Blockers

• Mechanism: Competitive antagonists of $\text{ACh}$ at muscarinic receptors (non-selective or M3-selective) $\rightarrow$ block $G_q$ protein $\rightarrow \downarrow \text{IP}_3/\text{DAG} \rightarrow \downarrow \text{Ca}^{2+} \rightarrow$ bronchodilation & $\downarrow$ mucus secretion.

• Classification & Comparison:

  Feature	SAMA (Short-Acting)	LAMA (Long-Acting)
  Examples	Ipratropium bromide	Tiotropium, Glycopyrronium, Aclidinium, Umeclidinium
  Receptor Sel.	Non-selective	Some are M3-selective
  Duration	4-6h	12-24h
  Key Uses (COPD)	Rescue in exacerbations	Maintenance therapy (mainstay)
  Key Uses (Asthma)	Acute severe asthma (with SABA)	Add-on therapy for severe asthma

  📌 Mnemonics:

  • Ipratropium: 'I PRAY I can breathe'
  • Tiotropium: 'TIOtropium = Take It Once' (daily)

• Uses:

  • COPD (mainstay for SAMA/LAMA).
  • Asthma (SAMA in acute severe asthma; LAMA as add-on).

• Adverse Effects:

  • Dry mouth (most common), metallic taste, pharyngeal irritation.
  • Systemic effects rare (quaternary ammonium compounds, poor absorption): urinary retention, tachycardia, blurred vision, acute angle-closure glaucoma (nebulizer mask leak).

⭐ Antimuscarinics are generally more effective in COPD than in asthma due to the greater role of vagal tone in COPD pathophysiology.

Methylxanthines - The Old Guard

• Examples: Theophylline, Aminophylline.
• Mechanism:
  • PDE inhibition (PDE3,4,5): $\uparrow \text{cAMP} + \uparrow \text{cGMP} \rightarrow$ bronchodilation.
  • Adenosine (A1,A2) antagonism $\rightarrow$ bronchodilation.
  • Anti-inflammatory (HDAC2 activation).
• Uses: 3rd-line asthma/COPD.
• NTI: 10-20 mg/L (55-110 µmol/L). 📌 'THEOphylline = TOXIC narrow window'. 
• AEs: GI (N/V/D), CNS (headache, seizures), Cardiac (tachycardia, arrhythmias).
• DIs (CYP1A2/3A4): 📌 'SMOKERS need MORE, SICK need LESS'.
  • Inhibitors ($\uparrow$ theo levels): Cimetidine, Macrolides, Cipro.
  • Inducers ($\downarrow$ theo levels): Rifampicin, Phenobarb, Smoking.

⭐ Smoking (CYP1A2 inducer) increases theophylline clearance, often needing 50-100% dose increase.

High‑Yield Points - ⚡ Biggest Takeaways

• β2-agonists (Salbutamol, Salmeterol) are primary bronchodilators for asthma and COPD.
• SABAs (Salbutamol) for acute relief; LABAs (Salmeterol) for long-term control with ICS.
• Anticholinergics (Ipratropium, Tiotropium) are key in COPD; Tiotropium is long-acting.
• Theophylline: narrow therapeutic index, potential toxicity, used as an adjunct.
• Mast cell stabilizers (Cromolyn): prophylactic in mild asthma, less potent than ICS.
• Omalizumab: anti-IgE antibody for severe allergic asthma.