Medical Pharmacology Chapter 6:  Autonomic Pharmacology: Cholinergic Drugs

• Bronchodilation

  • Bronchodilation following anticholinergic drug administration is due to blockade of acetylcholine effects on airway smooth muscle muscarinic receptors.

  • Extent of the response depends on vagal tone (pre-existing bronchomotor tone)

    • e.g. A clinical dose of scopolamine may decrease airway resistance and  increase dead space by about 1/3

  • Preferred Route of Administration for bronchodilation: aerosol

  • Ipratropium (Atrovent):anticholinergic drug most commonly used for aerosol administration -- synthetic quaternary ammonium atropine congener

    •  Most effective in preventing/treating bronchospasm due to ß-adrenergic antagonists

    •  More effective than ß-adrenergic agonists in producing bronchodilation in patients with chronic bronchitis or emphysema (high cholinergic tone)

    • Patients with bronchial asthma: usually respond better to  ß-agonist because of direct smooth muscle relaxation through β-receptor activation and by inhibition of histamine and leukotriene release (chemical mediators of smooth muscle contraction)

Stoelting, R.K., "Anticholinesterase Drugs and Cholinergic Agonists", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 241-244

• Gastrointestinal Tract

  • Vagal effects on the gut are mediated not only by acetylcholine but also by actions on intramural serotonergic and dopaminergic neurons.

  • Atropine can block Ach effects while having no effect on non-cholinergic modulation of GI motility.

  • Vagal input affects gastrin release and may be blocked by atropine; however, gastric acid release is more effectively prevented by M₁ specific antimuscarinic drugs (pirenzapine) and H₂-selective histamine receptor blockers.

Brown, J.H and Taylor, P. Muscarinic Receptor Agonists and Antagonists In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.149-159.

• Respiratory Tract

  • Parasympathetic activity produces bronchoconstriction.

  • Activation of nicotinic and M₁-muscarinic receptors is parasympathetic ganglia which lie in the airway wall then activate postganglionic fibers.

  • These postganglionic fibers release acetylcholine which activate M₃ muscarinic receptors which produce bronchiolar smooth muscle contraction.

    • M₂ receptors may also be present.

  • Muscarinic antagonists attenuate pulmonary smooth muscle constriction, often resulting in bronchodilation.

    • The magnitude of the effect depends on the basal parasympathetic tone.

    • Ipratropium bromide has been prominent in treating respiratory disease.

• Atropine and other antimuscarinic inhibit mouth, bronchial, and pharyngeal secretion which reduce reflex laryngospasm during general anesthesia.

  • Also, atropine or other antimuscarinics are given during general anesthesia to blunt increases in vagal tone due to mechanical effects on viscera during abdominal surgeries.

• Antimuscarinics, especially ipratropium, along with sympathomimetics, are useful in management of asthma. Ipratropium (Atrovent) has an advantage in asthma compared to atropine because:

  • Ipratropium does not inhibit mucociliary clearance (atropine does)

  • Ipratropium has no significant CNS effects.

  • Inhaled ipratropium (a quaternary, charge molecule) has limited or no systemic effects.

  • Ipratropium is more effective that beta-adrenergic agonists in COPD (cholinergic tone may be the only component that may be attenuated)

• Ophthalmological

  • Muscarinic receptor antagonists block parasympathetic responses of the ciliary muscle and iris sphincter muscle, resulting in paralysis of accommodation (cycloplegia) and mydriasis (pupillary dilation).

  • Mydriasis results in photophobia, whereas cycloplegia fixes the lens for far vision only (near objects appear blurred).

  • Systemic atropine at usual doses does not produce significant ophthalmic effect.

  • By contrast, systemic scopolamine results in both mydriasis and cycloplegia.

    • Note that sympathomimetic-induced mydriasis occurs without loss of accommodation.

  • Atropine-like drugs can increase intraocular pressure, sometimes dangerously, in patients with narrow-angle glaucoma.

  • Increases in intraocular pressure is not typical in wide-angle glaucoma.

• Cholinergic Blockers: Adverse effects

  •  Dry mouth (xerostromia)

  •  Blurred vision (cycloplegia)

  •  Photophobia (mydriasis) 

• Ganglion Blocking Drugs

  • Ganglionic blockers act mainly at the primary nicotinic-type cholinergic receptor at sympathetic and parasympathetic autonomic ganglia.

    • Agents which are classified as ganglionic blockers are not included among those drugs which block neuromuscular junctions.

  • One class of blocker produces a depolarization block.

    •  Nicotine could produce this effect.

  • The second class of agents include hexamethonium and trimethaphan.

    • These agents either competitively block the receptor or block the open channel configuration.

  • For essential hypertension, ganglionic blockers have been replaced by better drugs.

    • Ganglionic blockers may be used for initial blood pressure control in patients with dissecting aortic aneurysm because, in addition to reducing blood pressure, blunting of sympathetic responses reduce sheer forces at the tear.

  Taylor, P. Agents Acting at the Neuromuscular Junction and Autonomic Ganglia In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.193-195

Taylor, P. Agents Acting at the Neuromuscular Junction and Autonomic Ganglia In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.193-195. Adapted from Table 9-3.